Tofacitinib oral sustained release dosage forms

ABSTRACT

The present invention relates to oral sustained release formulations of tofacitinib and pharmaceutical acceptable salts thereof. The formulations described herein have desirable pharmacokinetic characteristics.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority from U.S. ProvisionalPatent Application No. 61/802,479, filed Mar. 16, 2013, U.S. ProvisionalPatent Application No. 61/864,059, filed Aug. 9, 2013, and U.S.Provisional Patent Application No. 61/934,428, filed Jan. 31, 2014.

FIELD OF THE INVENTION

The present invention relates to oral sustained release compositions of3-((3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3-oxopropionitrile(hereinafter tofacitinib), which is useful as an inhibitor of proteinkinases, such as the enzyme Janus Kinase (JAK) and as such are usefultherapy as immunosuppressive agents for organ transplants, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis,psoriasis, psoriatic arthritis, Type I diabetes and complications fromdiabetes, cancer, asthma, atopic dermatitis, autoimmune thyroiddisorders, ulcerative colitis, ankylosing spondylitis, juvenileidiopathic arthritis Crohn's disease, Alzheimer's disease, Leukemia, andother indications where immunosuppression would be desirable. Theinvention provides sustained release formulations comprising tofacitinibor pharmaceutically acceptable salts thereof. The formulations describedherein have desirable pharmacokinetic characteristics. Examples includeAUC, C_(max), dose-adjusted AUC, dose-adjusted C_(max), and fed/fastedAUC and C_(max) ratios.

BACKGROUND OF THE INVENTION

Tofacitinib,3-((3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3-oxopropionitrile,has the chemical formula C₁₆H₂₀N₆O and the following structural formula

The term “tofacitinib” should be understood, unless otherwise indicatedherein, to include any pharmaceutically acceptable form and salts of thecompound. Tofacitinib may be present in a crystalline or amorphous form.Tofacitinib, salts of tofacitinib, methods for synthesizing tofacitinib,certain polymorphs of tofacitinib, and certain uses of tofacitinib aredisclosed in WO01/42246, WO02/096909, and WO03/048162.

Tofacitinib is generally known to be useful as an inhibitor of proteinkinases, such as the enzyme Janus Kinase (JAK) and as such are usefultherapy as immunosuppressive agents for organ transplants, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis,psoriasis, psoriatic arthritis, Type I diabetes and complications fromdiabetes, cancer, asthma, atopic dermatitis, autoimmune thyroiddisorders, ulcerative colitis, Crohn's disease, Alzheimer's disease,Leukemia and other indications where immunosuppression would bedesirable.

Tofacitinib is being developed as an immediate release tablet form withdoses ranging from 5 mg to 10 mg administered BID (two times a day).Tofacitinib, as the citrate salt of tofacitinib, is approved in the USunder the brand XELJANZ™. Pharmaceutical dosage forms of tofacitinib areknown and described in WO01/42246, WO02/096909, and WO03/048162. Inaddition, WO2012/100949 purports to describe a modified releaseformulation of tofacitinib. While WO2012/100949 mentions thattofacitinib might be formulated in a modified release formulation,desirable pharmacokinetic characteristics have not been disclosed.

While the commercial immediate release tablet dosage form providesefficacious blood levels of tofacitinib to subjects (dictated by theaverage blood plasma concentration of tofacitinib, C_(ave), over a 24hour period), it may be possible to reduce the number of dosings to oncedaily (QD) with a sustained-release dosage form of tofacitinib whilemaintaining consistent therapeutic effect, thus enhancing convenienceand potentially improving compliance.

Sustained-release dosage forms are typically designed to provide thelongest possible duration of release, to minimize: 1) the fluctuationsin blood plasma concentration during the dosing interval (i.e. the ratioof the maximum blood plasma concentration, C_(max,ss), to the minimumblood plasma concentration, C_(min,ss), during the dosing interval), and2) the amount of drug required to achieve the desired therapeuticeffect, for the purpose of improving the safety and tolerabilityprofile. For example, WO2012/100949 purports to describe a modifiedrelease formulation of tofacitinib having the advantage that tofacitinibis gradually released over a relatively long period at a uniformconcentration, which results in little blood level fluctuation in thepatient.

However, it was surprisingly found that the bioavailability oftofacitinib is reduced as the duration of release is prolonged, therebyrequiring increased amounts of tofacitinib to be administered in thesustained release dosage form to provide efficacious blood levels tosubjects.

In addition, the pharmacokinetic profile of the BID immediate releasetablets contains periods during a 24 hour time period beneath the 1050for the JAK1/3 heterodimer signaling (“Drug Holiday”), due to thecombination of total drug absorbed and the ratio of the maximum bloodplasma concentration, C_(max,ss), to the minimum blood plasmaconcentration, C_(min,ss), during the dosing interval. Tofacitinib is aselective inhibitor of the Janus kinase (JAK) family of kinases with ahigh degree of selectivity against other kinases in the human genome. Inkinase assays, tofacitinib inhibits JAK1, JAK2, JAK3, and to a lesserextent tyrosine kinase (TyK2). In cellular settings, where JAK kinasessignal in pairs, tofacitinib preferentially inhibits cytokines thatsignal through JAK3 and/or JAK1 including interleukin (IL)-2, -4, -6,-7, -9, -15, -21, and type I and II interferons. These cytokines arepro-inflammatory and integral to lymphocyte function. Inhibition oftheir signaling may thus result in modulation of multiple aspects of theimmune response. Over inhibition of signaling through JAK3 and/or JAK1could compromise the body's immune system.

It was surprisingly found that the drug holiday period of tofacitinibrelative to the IC50 for JAK1/3 signaling during a 24 time period isincreased as the release duration from a sustained release dosage formis prolonged. As such, sustained release dosage forms, as described inthe prior art, containing tofacitinib would not provide drug holidayperiods comparable to the PK profile of the BID immediate releasetablets, due to the reduced blood plasma concentrations of tofacitinibexhibited by sustained release dosage forms, as described by the priorart. Accordingly, it was surprisingly found that to provide the optimalPK profile (i.e. optimal exposure and optimal C_(max,ss)/C_(min,ss)ratio while avoiding elevated levels of the maximum blood plasmaconcentration) for once-daily administration of tofacitinib, dosageforms with shorter durations of sustained release are preferred. It wasalso surprisingly found that to minimize the total dose of tofacitinibadministered to subjects while providing efficacious blood levels insubjects, dosage forms with shorter durations of sustained release arepreferred.

SUMMARY OF THE INVENTION

The present invention relates to oral sustained release compositions oftofacitinib for the treatment of anti-inflammatory and auto-immunediseases, and especially Rheumatoid Arthritis (RA). Sustained release oftofacitinib may be accomplished by any means known in the pharmaceuticalarts, including but not limited to the use of osmotic dosage forms,matrix dosage forms, multiparticulate dosage forms, gastric retentivedosage forms, and pulsatile dosage forms.

The present invention provides a once daily pharmaceutical dosage formcomprising tofacitinib, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier, wherein said dosage form is asustained release dosage form, and when administered to a subject has amean area under the plasma concentration versus time curve followingadministration from about 27 ng-hr/mL per mg of tofacitinib dosed toabout 42 ng-hr/mL per mg of tofacitinib dosed and a ratio of geometricmean plasma Cmax to Cmin from about 10 to about 100, preferably theratio of geometric mean plasma Cmax to Cmin from about 20 to about 40and more preferably from about 20 to about 30. The pharmaceutical dosageform may comprise from about 10 mg to about 12 mg of tofacitinib,preferably 11 mg of tofacitinib. In another embodiment, thepharmaceutical dosage form may comprise from about 20 to about 24 mg oftofacitinib, preferably 22 mg of tofacitinib. The pharmaceutical dosageform of the invention also provides the subject a single, continuoustime above about 17 ng/ml from about 6 to about 15 hours and a single,continuous time below about 17 ng/ml from about 9 to about 18 hours overa 24 hour dosing interval. In another embodiment of the invention, thesubject has a single, continuous time above about 17 ng/ml from about 6to about 9 hours. In another embodiment of the invention, the subjecthas a single, continuous time below about 17 ng/ml from about 15 toabout 18 hours. In another embodiment of the invention, the subject hasa single, continuous time above about 17 ng/ml from about 11 to about 15hours. In another embodiment of the invention, the subject has a single,continuous time below about 17 ng/ml from about 9 to about 13 hours. Inanother embodiment, the pharmaceutical dosage form of the presentinvention may provide a subject having a mean maximum plasmaconcentration (Cmax) from about 3 ng/mL per mg to about 6 ng/mL per mgof tofacitinib dosed.

The present invention also provides a once daily pharmaceutical dosageform comprising tofacitinib, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, wherein said dosageform is a sustained release dosage form, and when administered to asubject has a mean area under the plasma concentration versus time curvefollowing administration from about 17 ng-hr/mL per mg of tofacitinibdosed to about 42 ng-hr/mL per mg of tofacitinib dosed and a ratio ofgeometric mean plasma Cmax to Cmin from about 10 to about 100,preferably the ratio of geometric mean plasma Cmax to Cmin from about 20to 40 and more preferably about 20 to 30. The pharmaceutical dosage formmay comprise from about 10 mg to about 12 mg of tofacitinib, preferably11 mg of tofacitinib. In another embodiment, the pharmaceutical dosageform may comprise from about 20 to about 24 mg of tofacitinib,preferably 22 mg of tofacitinib. The pharmaceutical dosage form of theinvention also provides the subject a single, continuous time aboveabout 17 ng/ml from about 6 to about 15 hours and a single, continuoustime below about 17 ng/ml from about 9 to about 18 hours over a 24 hourdosing interval. In another embodiment of the invention, the subject hasa single, continuous time above about 17 ng/ml from about 6 to about 9hours. In another embodiment of the invention, the subject has a single,continuous time below about 17 ng/ml from about 15 to about 18 hours. Inanother embodiment of the invention, the subject has a single,continuous time above about 17 ng/ml from about 11 to about 15 hours. Inanother embodiment of the invention, the subject has a single,continuous time below about 17 ng/ml from about 9 to about 13 hours. Inanother embodiment, the pharmaceutical dosage form of the presentinvention may provide a subject having a mean maximum plasmaconcentration (Cmax) from about 3 ng/mL per mg to about 6 ng/mL per mgof tofacitinib dosed.

The present invention additionally provides a once daily pharmaceuticaldosage form comprising tofacitinib, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier, wherein saiddosage form is a sustained release dosage form, and when administeredorally to a subject has a mean steady-state minimum plasma concentration(Cmin) less than about 0.3 ng/mL per mg of tofacitinib dosed.

In another embodiment, the present invention provides a once dailypharmaceutical dosage form comprising tofacitinib, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,wherein said dosage form is a sustained release dosage form, and whenadministered orally to a subject has a mean fed/fasted ratio of the areaunder the plasma concentration versus time curve of about 0.7 to about1.4 and a mean fed/fasted ratio of the maximum plasma concentration(Cmax) of about 0.7 to about 1.4, preferably about 0.8 to about 1.25.

In another embodiment, the present invention provides a pharmaceuticaldosage form comprising tofacitinib, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier, wherein saiddosage form is a sustained release dosage form, and when added to a testmedium comprising 900 mL of 0.05M pH 6.8 potassium phosphate buffer at37° C. in a standard USP rotating paddle apparatus and the paddles arerotated at 50 rpm, dissolves not more than 30% of the drug in 1 hour,and not less than 35% and not more than 75% of the drug in 2.5 hours andnot less than 75% of the tofacitinib in 5 hours; preferably not morethan 25% of the drug in 1 hour, and not less than 40% and not more than70% of the drug in 2.5 hours.

In another embodiment, the present invention provides a pharmaceuticaldosage form comprising tofacitinib, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier, wherein thedosage form is a sustained release dosage form and when administeredorally to a subject provides an AUC in the range of 80% to 125% of theAUC of an amount of tofacitinib administered as an immediate releaseformulation BID and wherein the sustained release dosage form provides aratio of geometric mean plasma Cmax to Cmin from about 10 to about 100,preferably the AUC may be in the range of 90% to 110% and the ratio ofgeometric mean plasma concentration Cmax to Cmin may be from about 20 toabout 40 and more preferably from about 20 to about 30.

In another embodiment, the pharmaceutical dosage form of the presentinvention may also provide a mean plasma Cmax in the range of 70% to125% of the mean plasma Cmax of tofacitinib administered as an immediaterelease formulation BID at steady state when administered orally to asubject. In another embodiment, the pharmaceutical dosage form of thepresent invention provides a drug holiday in the range of 80% to 110% ofthe drug holiday of tofacitinib administered as an immediate releaseformulation BID over a 24 hour period when administered orally to asubject. The pharmaceutical dosage form of the present invention maycomprise from about 10 mg to about 12 mg of tofacitinib and theequivalent amount of tofacitinib administered as an immediate releaseformulation BID is 5 mg, preferably the pharmaceutical dosage formcomprises 11 mg of tofacitinib. The pharmaceutical dosage form of thepresent invention may comprise from about 20 mg to about 24 mg oftofacitinib and the equivalent amount of tofacitinib administered as theimmediate release formulation BID is 10 mg, preferably thepharmaceutical dosage form may comprise 22 mg of tofacitinib. In ananother embodiment, the pharmaceutical dosage form of the presentinvention provides the drug holiday from about 15 to about 18 hours overthe 24 hour period. In an another embodiment, the pharmaceutical dosageform of the present invention provides the drug holiday from about 9 toabout 13 hours over the 24 hour period.

The present invention also provides for pharmaceutical compositions toachieve these sustained delivery formulations. In one embodiment, thesustained release pharmaceutical dosage form of the present inventioncomprising a core containing tofacitinib, or a pharmaceuticallyacceptable salt thereof, and a semi-permeable membrane coating whereinsaid coating comprises substantially of a water-insoluble polymer. Thesustained release dosage form of the present invention may delivertofacitinib primarily by osmotic pressure. In another embodiment of thepresent invention, the sustained release dosage form of the presentinvention may comprise a delivery system selected from the groupconsisting of an extrudable core system, swellable core system, orasymmetric membrane technology.

In another embodiment, the water insoluble polymer comprises a cellulosederivative, preferably cellulose acetate. In another embodiment of thepresent invention, the coating further comprising a water solublepolymer having an average molecular weight between 2000 and 100,000daltons. In another embodiment of the present invention the watersoluble polymer is selected from the group consisting of water solublecellulose derivatives, acacia, dextrin, guar gum, maltodextrin, sodiumalginate, starch, polyacrylates, and polyvinyl alcohols. In anotherembodiment of the present invention, the water soluble cellulosederivatives comprises hydroxypropylcellulose,hydroxypropylmethylcellulose or hydroxyethylcellulose.

In another embodiment of the present invention, the core comprises asugar, preferably sorbitol.

In another embodiment the sustained release pharmaceutical dosage formof the present invention, comprising tofacitinib, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrierwherein said tofacitinib is embedded in a matrix which releasestofacitinib by diffusion. In one embodiment, a portion of the outsidesurface of the matrix is covered with an impermeable coating and theremainder of the outside surface is uncovered.

In another embodiment of the present invention, the dosage form is inthe form of a tablet and the uncovered surface is in the form of anopening through the impermeable coating.

In another embodiment of the present invention, the dosage form is inthe form of a tablet and the uncovered surface is in the form of apassageway which penetrates through the entire tablet.

In another embodiment of the present invention, the dosage form is inthe form of a tablet and the uncovered surface is in the form of one ormore slits through said impermeable coating or in the form of one ormore strips removed therefrom.

In another embodiment of the present invention, the matrix of the dosageform remains substantially intact during the period of tofacitinibrelease.

In another embodiment of the present invention, the pharmaceuticallyacceptable carrier comprising the matrix material is selected from thegroup consisting of waxes, long chain alcohols, fatty acid esters,glycolized fatty acid esters, phosphoglycerides, polyoxyethylene alkylethers, long chain carboxylic acids, sugar alcohols, and mixturesthereof.

In another embodiment of the present invention, the outside surface ofsaid matrix is covered with an enteric coating. The matrix may be formedas a melt-congealed core.

In another embodiment of the present invention, the matrix of the dosageform comprises hydroxypropyl methylcellulose.

In another embodiment of the present invention, tofacitinib is embeddedin a matrix which releases tofacitinib by eroding.

In another embodiment of the present invention, the matrix of the dosageform comprises hydroxypropyl methylcellulose.

In another embodiment of the present invention, the matrix of the dosageform comprises poly(ethylene oxide).

In another embodiment of the present invention, the matrix of the dosageform comprises polyacrylic acid.

In another embodiment of the present invention, a reservoir oftofacitinib is encased in a membrane which limits the release rate oftofacitinib by diffusion.

In another embodiment the sustained release pharmaceutical dosage formof the present invention provides a dosage form in the form of a tabletcoated with a membrane.

In another embodiment the sustained release pharmaceutical dosage formof the present invention provides a dosage form in the form of amultiparticulate comprising particles, which particles are independentlycoated with a membrane which limits the release rate of tofacitinib bydiffusion.

The present invention also provides a method of treating immunologicaldisorders in a subject comprising administering to the subject in needthereof the sustained release pharmaceutical dosage form of the presentinvention in an amount effective in treating such disorders. Theimmunological disorder is selected from the group consisting of organtransplants, xeno transplantation, lupus, multiple sclerosis, rheumatoidarthritis, psoriasis, Type I diabetes and complications from diabetes,cancer, asthma, atopic dermatitis, autoimmune thyroid disorders,ulcerative colitis, ankylosing spondylitis, juvenile idiopathicarthritis Crohn's disease, psoriatic arthritis, Alzheimer's disease, andLeukemia, preferably, the immunological disorder is selected from thegroup consisting of organ transplant, rheumatoid arthritis, psoriasis,psoriatic arthritis, ulcerative colitis, ankylosing spondylitis,juvenile idiopathic arthritis and Crohn's disease. In another embodimentof the present invention the method further comprising one or moreadditional agents which modulate a mammalian immune system or withanti-inflammatory agents. The additional agent may be selected from thegroup consisting of a nonbiologic DMARD, methotrexate, glucocorticoid,glucocorticoid receptor agonist, leflunomide, non-steroidalanti-inflammatory drugs, 6-mercaptopurine, azathioprine, sulfasalazine,and 5-aminosalicylate drugs, preferably the additional agent is selectedfrom the group consisting of a nonbiologic DMARD and a glucocorticoidreceptor agonist, more preferably the additional agent is methotrexate.

The present invention also provides a method of treating atherosclerosisin a subject comprising administering to the subject in need thereof thesustained release pharmaceutical of the present invention in an amounteffective in treating atherosclerosis. In another embodiment of thepresent invention, the method further comprises administering a HMG-CoAreductase inhibitor, preferably the HMG-CoA reductase inhibitor isatorvastatin or a pharmaceutically acceptable salt thereof.

The term “tofacitinib” should be understood, unless otherwise indicatedherein, to include any pharmaceutically acceptable form and salts of thecompound. Tofacitinib may be present in crystalline or amorphous form.The present invention relates to a sustained release dosage form oftofacitinib to enable once a day administration to provide specificpharmacokinetic properties for the purpose of: 1) minimizing the amountof tofacitinib in the sustained release dosage form required to achieveefficacious blood levels in subjects, 2) optimizing the extent oftofacitinib binding to the JAK 1/3 heterodimers (as measured by IC₅₀,which occurs in humans at drug plasma concentrations of about 17 ng/mlor 56 nM as reported in Meyer D M, Jesson M I, Xiong L, et al.Anti-inflammatory activity and neutrophil reduction mediated by theJAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis J. ofInflammation 2010; 7:41, which is incorporated herein by reference),which regulates the immune response, to provide the desired level ofefficacy (based on the mean C_(ave)) over a 24-hour dosing interval. Thesustained release dosage form of the present invention is one thatprovides the above desired pharmacokinetic properties, and in particularthe once daily dosage properties recited above. Preferably the sustainedrelease dosage form of the invention does not significantly alter thepharmacokinetic profile of tofacitinib when administered in the fedstate (i.e. exhibits a lack of food effect), as this minimizes deviationfrom the optimal coverage of JAK 1/3 heterodimers.

By “sustained release” is meant broadly that tofacitinib is releasedfrom an oral dosage form at a rate that is slower than immediaterelease. Oral dosage form is intended to embrace tablets, capsules,multiparticulates or beads. “Sustained release” is intended to embracean oral composition that consists of either one or a combination of thefollowing:

a) a controlled release component alone;

b) a delayed release and controlled release component;

c) a delayed release and immediate release component

By “pharmaceutically acceptable form” is meant any pharmaceuticallyacceptable form, including, solvates, hydrates, isomorphs, polymorphs,co-crystals, pseudomorphs, neutral forms, acid addition salt forms, andprodrugs. The pharmaceutically acceptable acid addition salts oftofacitinib are prepared in a conventional manner by treating a solutionor suspension of the free base with about one or two chemicalequivalents of a pharmaceutically acceptable acid. Conventionalconcentration and recrystallization techniques are employed in isolatingthe salts. Illustrative of suitable acids are acetic, lactic, succinic,maleic, tartaric, citric, gluconic, ascorbic, mesylic, tosylic, benzoic,cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic,hydroiodic, sulfamic, sulfonic such as methanesulfonic, benzenesulfonic,and related acids. Some preferred forms of tofacitinib include the freebase and tofacitinib citrate.

The terms “subject”, “patient” and “individual” are used interchangeablyherein to refer to a vertebrate, preferably a mammal, more preferably ahuman.

The “solid oral dosage form” of the present invention is apharmaceutically-acceptable solid oral dosage form, meaning that thedosage form is safe for administration to humans and all excipients inthe dosage form are pharmaceutically-acceptable, in other words safe forhuman ingestion.

The term “fasted” as used herein is defined as follows: the dosing statewhich is defined following an overnight fast (wherein 0 caloric intakehas occurred) of at least 10 hours. Subjects may administer the dosageform with 240 mL of water. No food should be allowed for at least 4hours post-dose. Water may be allowed as desired except for one hourbefore and after drug administration.

The term “fed” as used herein is defined as follows: the dosing statewhich is defined following an overnight fast (wherein 0 caloric intakehas occurred) of at least 10 hours, subjects then begin the recommendedhigh fat meal 30 minutes prior to administration of the drug product.Subjects should eat this meal in 30 minutes or less; however the drugproduct should be administered 30 minutes after the start of the meal.The drug product may be administered with 240 mL of water. No foodshould be allowed for at least 4 hours post-dose. Water may be allowedas desired except for one hour before and after drug administration. Ahigh fat (approximately 50 percent of the total caloric content of themeal is derived from fat) and high calorie (approximately 800 to 1000calories) meal should be used as the test meal under the fed condition.This test meal should derive approximately 150, 250, and 500-600calories from protein, carbohydrate, and fat respectively. An exampletest meal would be two eggs fried in butter, two strips of bacon, twoslices of toast with butter, four ounces of hash brown potatoes andeight ounces of whole milk.

The calculation of the mean area under the serum concentration versustime curve (AUC) is a well-known procedure in the pharmaceutical artsand is described, for example, in Welling, “Pharmacokinetics Processesand Mathematics,” ACS Monograph 185 (1986). AUC as used herein includesarea under the concentration-time curve from time zero extrapolated toinfinite time following single dose or the area under theconcentration-time curve from time zero to time of the end of dosinginterval following steady state/multiple dose. In addition, thecalculations for C_(max), C_(min,ss), T_(max), and elimination half-life(t½), are also known to this of ordinary skill in the art and isdescribed, for example, in Shargel, Wu-Pong, and Yu, AppliedBiopharmaceutics and Pharmacokinetics (2005). To determine the meanfed/fasted ratio, the individual ratio of the mean area under the plasmaconcentration versus time curve of tofacitinib (e.g. AUC_(0-inf)) in thefed state to the mean area under the plasma concentration versus timecurve of tofacitinib (e.g. AUC_(0-inf)) in the fasted state is firstcalculated, and then the corresponding individual ratios are averagedtogether. In this way, it is the average of each correspondingindividual's ratio which is determined.

“Dissolution Test 1” refers to the following test of dosage forms oftofacitinib. The dissolution test is conducted in a standard USProtating paddle apparatus as disclosed in United States Pharmacopoeia(USP) Dissolution Test Chapter 711, Apparatus 2. Paddles are rotated at50 rpm and the dosage form is added to 900 mL of 0.05M pH 6.8 potassiumphosphate buffer at 37° C. At appropriate times following testinitiation (e.g., insertion of the dosage form into the apparatus),filtered aliquots (typically 1.5 mL) from the test medium are analyzedfor tofacitinib by high performance liquid chromatography (HPLC).Dissolution results are reported as the percent of the total dose oftofacitinib tested dissolved versus time.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to oral sustained release compositions oftofacitinib for the treatment of anti-inflammatory and auto-immunediseases, and especially Rheumatoid Arthritis (RA). Sustained release oftofacitinib may be accomplished by any means known in the pharmaceuticalarts, including but not limited to the use of osmotic dosage forms,matrix dosage forms, multiparticulate dosage forms, gastric retentivedosage forms, and pulsatile dosage forms.

Sustained Release—Matrix Systems (Tablets)

In one embodiment, tofacitinib is incorporated into an erodible ornon-erodible polymeric matrix tablet. By an erodible matrix is meantaqueous-erodible or water-swellable or aqueous-soluble in the sense ofbeing either erodible or swellable or dissolvable in pure water orrequiring the presence of an acid or base to ionize the polymeric matrixsufficiently to cause erosion or dissolution. When contacted with theaqueous use environment, the erodible polymeric matrix imbibes water andforms an aqueous-swollen gel or “matrix” that entraps the tofacitinib.The aqueous-swollen matrix gradually erodes, swells, disintegrates,disperses or dissolves in the environment of use, thereby controllingthe release of tofacitinib to the environment of use. Examples of suchdosage forms are well known in the art. See, for example, Remington: TheScience and Practice of Pharmacy, 20^(th) Edition, 2000.

A key ingredient of the water-swollen matrix is the water-swellable,erodible, or soluble polymer, which may generally be described as anosmopolymer, hydrogel or water-swellable polymer. Such polymers may belinear, branched, or crosslinked. They may be homopolymers orcopolymers. Exemplary polymers include naturally occurringpolysaccharides such as chitin, chitosan, dextran and pullulan; gumagar, gum arabic, gum karaya, locust bean gum, gum tragacanth,carrageenans, gum ghatti, guar gum, xanthan gum and scleroglucan;starches such as dextrin and maltodextrin; hydrophilic colloids such aspectin; alginates such as ammonium alginate, sodium, potassium orcalcium alginate, propylene glycol alginate; gelatin; collagen; andcellulosics. By “cellulosics” is meant a cellulose polymer that has beenmodified by reaction of at least a portion of the hydroxyl groups on thesaccharide repeat units with a compound to form an ester-linked or anether-linked substituent. For example, the cellulosic ethyl cellulosehas an ether linked ethyl substituent attached to the saccharide repeatunit, while the cellulosic cellulose acetate has an ester linked acetatesubstituent.

Cellulosics for the erodible matrix comprise aqueous-soluble andaqueous-erodible cellulosics such as ethyl cellulose (EC), methylethylcellulose (MEC), carboxymethyl cellulose (CMC), carboxymethylethylcellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate phthalate (CAP), cellulose acetatetrimellitate (CAT), hydroxypropyl methyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropyl methyl celluloseacetate succinate (HPMCAS), hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC).

A particularly preferred class of such cellulosics comprises variousgrades of low viscosity (MW less than or equal to 50,000 daltons) andhigh viscosity (MW greater than 50,000 daltons) HPMC. Commerciallyavailable low viscosity HPMC polymers include the Dow METHOCEL™ seriesE3, E5, E15LV, E50LV and K100LV, while high viscosity HPMC polymersinclude E4MCR, E10MCR, K4M, K15M and K100M; especially preferred in thisgroup are the METHOCEL™ K series. Other commercially available types ofHPMC include the Shin Etsu METOLOSE™ 90SH series. In one embodiment, theHPMC has a low viscosity, meaning that the viscosity of a 2% (w/v)solution of the HPMC in water is less than about 120 cp. A preferredHPMC is one in which the viscosity of a 2% (w/v) solution of the HPMC inwater ranges from 80 to 120 cp (such as METHOCEL™ K100LV).

Other materials useful as the erodible matrix material include, but arenot limited to, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol,polyvinyl acetate, glycerol fatty acid esters, polyacrylamide,polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid(EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.) and other acrylic acidderivatives such as homopolymers and copolymers of butylmethacrylate,methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

The erodible matrix polymer may also contain additives and excipientsknown in the pharmaceutical arts, including osmopolymers, osmagens,solubility-enhancing or -retarding agents and excipients that promotestability or processing of the dosage form.

In a non-erodible matrix system, tofacitinib is distributed in an inertmatrix. The drug is released by diffusion through the inert matrix.Examples of materials suitable for the inert matrix include insolubleplastics, such as copolymers of ethylene and vinyl acetate, methylacrylate-methyl methacrylate copolymers, polyvinyl chloride, andpolyethylene; hydrophilic polymers, such as ethyl cellulose, celluloseacetate, and crosslinked polyvinylpyrrolidone (also known ascrospovidone); and fatty compounds, such as carnauba wax,microcrystalline wax, and triglycerides. Such dosage forms are describedfurther in Remington: The Science and Practice of Pharmacy, 20^(th)edition (2000).

Sustained Release—Matrix Systems (Multiparticulates)

In another embodiment, a matrix multiparticulate, comprises a pluralityof tofacitinib-containing particles, each particle comprising a mixtureof tofacitinib with one or more excipients selected to form a matrixcapable of limiting the dissolution rate of the tofacitinib into anaqueous medium. The matrix materials useful for this embodiment aregenerally water-insoluble materials such as waxes, cellulose, or otherwater-insoluble polymers. If needed, the matrix materials may optionallybe formulated with water-soluble materials which can be used as bindersor as permeability-modifying agents. Matrix materials useful for themanufacture of these dosage forms include microcrystalline cellulosesuch as Avicel (registered trademark of FMC Corp., Philadelphia, Pa.),including grades of microcrystalline cellulose to which binders such ashydroxypropyl methyl cellulose have been added, waxes such as paraffin,modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax,and the like, as well as synthetic polymers such as poly(vinylchloride), poly(vinyl acetate), copolymers of vinyl acetate andethylene, polystyrene, and the like. Water soluble binders or releasemodifying agents which can optionally be formulated into the matrixinclude water-soluble polymers such as hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), methyl cellulose,poly(N-vinyl-2-pyrrolidinone) (PVP), poly(ethylene oxide) (PEO),poly(vinyl alcohol) (PVA), xanthan gum, carrageenan, and other suchnatural and synthetic materials. In addition, materials which functionas release-modifying agents include water-soluble materials such assugars or salts. Preferred water-soluble materials include lactose,sucrose, glucose, and mannitol, as well as HPC, HPMC, and PVP.

A process for manufacturing matrix multiparticulates is theextrusion/spheronization process. For this process, the tofacitinib iswet-massed with a binder, extruded through a perforated plate or die,and placed on a rotating disk. The extrudate ideally breaks into pieceswhich are rounded into spheres, spheroids, or rounded rods on therotating plate. Another process and composition for this method involvesusing water to wet-mass a blend comprising about 20 to 75% ofmicro-crystalline cellulose blended with, correspondingly, about 80 to25% tofacitinib.

Another process for manufacturing matrix multiparticulates is thepreparation of wax granules. In this process, a desired amount oftofacitinib is stirred with liquid wax to form a homogeneous mixture,cooled and then forced through a screen to form granules. Preferredmatrix materials are waxy substances. Some preferred waxy substances arehydrogenated castor oil and carnauba wax and stearyl alcohol.

A further process for manufacturing matrix multiparticulates involvesusing an organic solvent to aid mixing of the tofacitinib with thematrix material. This technique can be used when it is desired toutilize a matrix material with an unsuitably high melting point that, ifthe material were employed in a molten state, would cause decompositionof the drug or of the matrix material, or would result in anunacceptable melt viscosity, thereby preventing mixing of tofacitinibwith the matrix material. Tofacitinib and matrix material may becombined with a modest amount of solvent to form a paste, and thenforced through a screen to form granules from which the solvent is thenremoved. Alternatively, tofacitinib and matrix material may be combinedwith enough solvent to completely dissolve the matrix material and theresulting solution (which may contain solid drug particles) spray driedto form the particulate dosage form. This technique is preferred whenthe matrix material is a high molecular weight synthetic polymer such asa cellulose ether or cellulose ester. Solvents typically employed forthe process include acetone, ethanol, isopropanol, ethyl acetate, andmixtures of two or more.

In one embodiment, the matrix multiparticulates are formed by the meltspray congeal process. The melt-congeal core comprises a matrixmaterial. The matrix material serves two functions. First, the matrixmaterial allows formation of relatively smooth, round cores that areamenable to coating. Second, the matrix material binds the optionalexcipients and/or drugs that may be incorporated into the core. Thematrix material has the following physical properties: a sufficientlylow viscosity in the molten state to form multiparticulates, as detailedbelow; and rapidly congeals to a solid when cooled below its meltingpoint. For those multiparticulates incorporating drug in the core, thematrix preferably has a melting point below that of the melting point ordecomposition point of the drug, and does not substantially dissolve thedrug.

The melt-congeal cores consist essentially of a continuous phase ofmatrix material and optionally other excipients, with optional drugparticles and optional swelling agent particles encapsulated within.Because of this, a sufficient amount of matrix material must be presentto form smooth cores that are large enough to coat. In the case of corescontaining solid particles, such as drug or swelling agent, the coremust contain a sufficient amount of matrix material to encapsulate thedrug and swelling agent to form relatively smooth and spherical cores,which are more easily coated by conventional spray-coating processesthan irregularly-shaped ones. The matrix material may be present in thecore from at least about 30 wt percent, at least about 50 wt percent, atleast about 70 wt percent, at least about 80 wt percent, at least about90 wt percent, and up to 100 wt percent based on the mass of theuncoated core.

In order to form small, smooth round cores, the matrix material must becapable of being melted and then atomized. The matrix material ormixture of materials is solid at 25 degrees C. However, the matrixmaterial melts, or is capable of melting with the addition of anoptional processing aid, at a temperature of less than 200 degreescentigrade so as to be suitable for melt-congeal processing describedbelow. Preferably, the matrix material has a melting point between 50degrees C. and 150° C. Although the term “melt” generally refers to thetransition of a crystalline material from its crystalline to its liquidstate, which occurs at its melting point, and the term “molten”generally refers to such a crystalline material in its fluid state, asused herein, the terms are used more broadly. In the case of “melt,” theterm is used to refer to the heating of any material or mixture ofmaterials sufficiently that it becomes fluid in the sense that it may bepumped or atomized in a manner similar to a crystalline material in thefluid state. Likewise “molten” refers to any material or mixture ofmaterials that is in such a fluid state.

The matrix material is selected from the group consisting of waxes, longchain alcohols (Ci₂ 12 or greater), fatty acid esters, glycolized fattyacid esters, phosphoglycerides, polyoxyethylene alkyl ethers, long chaincarboxylic acids (Ci₂ 12 or greater), sugar alcohols, and mixturesthereof. Exemplary matrix materials include highly purified forms ofwaxes, such as Camauba wax, white and yellow beeswax, ceresin wax,microcrystalline wax, and paraffin wax; long-chain alcohols, such asstearyl alcohol, cetyl alcohol and polyethylene glycol; fatty acidesters (also known as fats or glycerides), such as isopropyl palmitate,isopropyl myristate, glyceryl monooleate, glyceryl monostearate,glyceryl palmitostearate, mixtures of mono-, di-, and trialkylglycerides, including mixtures of glyceryl mono-, di-, and tribehenate,glyceryl tristearate, glyceryl tripalmitate and hydrogenated vegetableoils, including hydrogenated cottonseed oil; glycolized fatty acidesters, such as polyethylene glycol stearate and polyethylene glycoldistearate; polyoxyethylene alkyl ethers; polyethoxylated castor oilderivatives; long-chain carboxylic acids such as stearic acid; and sugaralcohols such as mannitol and erythritol. The matrix material maycomprise mixtures of materials, such as mixtures of any of theforegoing.

The core may also contain a variety of other excipients, present in thecore in an amount of from 0 to 40 wt percent, based upon the mass of theuncoated core. One preferred excipient is a dissolution enhancer, whichmay be used to increase the rate of water uptake by the core andconsequent expansion of the swelling agent. The dissolution enhancer isa different material than the matrix material. The dissolution enhancermay be in a separate phase or a single phase with the matrix material.Preferably, at least a portion of the dissolution enhancer isphase-separated from the matrix material. As water enters the core, thedissolution-enhancer dissolves, leaving channels which allow water tomore rapidly enter the core. In general, dissolution enhancers areamphiphilic compounds and are generally more hydrophilic than the matrixmaterials. Examples of dissolution enhancers include: surfactants suchas poloxamers, docusate salts, polyoxyethylene castor oil derivatives,polysorbates, sodium lauryl sulfate, and sorbitan monoesters; sugars,such as glucose, xylitol, sorbitol and maltitol; salts, such as sodiumchloride, potassium chloride, lithium chloride, calcium chloride,magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate,magnesium sulfate and potassium phosphate; and amino acids, such asalanine and glycine; and mixtures thereof. One surfactant-typedissolution-enhancer is a poloxambetar (commercially available as theLUTROL or PLURONIC series from BASF Corp.).

The core may also contain other optional excipients, such as agents thatinhibit or delay the release of drug from the multiparticulates. Suchdissolution-inhibiting agents are generally hydrophobic and includedialkylphthalates such as dibutyl phthalate, and hydrocarbon waxes, suchas microcrystalline wax and paraffin wax. Another useful class ofexcipients comprises materials that may be used to adjust the viscosityof the molten feed used to form the cores. Such viscosity-adjustingexcipients will generally make up 0 to 25 wt percent of the core. Theviscosity of the molten feed is a key variable in obtaining cores with anarrow particle size distribution. For example, when a spinning-diskatomizer is employed, it is preferred that the viscosity of the moltenmixture be at least about 1 cp and less than about 10,000 cp, preferablyat least 50 cp and less than about 1000 cp. If the molten mixture has aviscosity outside these ranges, a viscosity-adjusting agent can be addedto obtain a molten mixture within the viscosity range. Examples ofviscosity-reducing excipients include stearyl alcohol, cetyl alcohol,low molecular weight polyethylene glycol (i.e., less than about 1000daltons), isopropyl alcohol, and water. Examples of viscosity-increasingexcipients include microcrystalline wax, paraffin wax, synthetic wax,high molecular weight polyethylene glycols (i.e., greater than about5000 daltons), ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, silicon dioxide, microcrystallinecellulose, magnesium silicate, sugars, and salts.

For those embodiments containing a drug in the core, other excipientsmay be added to adjust the release characteristics of the drug from thecores. For example, an acid or base may be included in the compositionto modify the rate at which drug is released in an aqueous useenvironment. Examples of acids or bases that can be included in thecomposition include citric acid, adipic acid, malic acid, fumaric acid,succinic acid, tartaric acid, di- and tribasic sodium phosphate, di- andtribasic calcium phosphate, mono-, di-, and triethanolamine, sodiumbicarbonate and sodium citrate dihydrate. Such excipients may make up 0to 25 wt percent of the core, based on the total mass of the core.

Still other excipients may be added to improve processing, such asexcipients to reduce the static charge on the cores or to reduce themelting temperature of the matrix material. Examples of such anti-staticagents include talc and silicon dioxide. Flavorants, colorants, andother excipients may also be added in their usual amounts for theirusual purposes. Such excipients may make up 0 to 25 wt percent of thecore, based on the total mass of the core.

The multiparticulates are made via a melt-congeal process comprising thesteps: (a) forming a molten mixture comprising the drug, the glyceride(or other waxes), and any release modifying agents; (b) delivering themolten mixture of step (a) to an atomizing means to form droplets fromthe molten mixture; and (c) congealing the droplets from step (b) toform multiparticulates.

The processing conditions are chosen to maintain the crystallinity ofthe drug. The temperature of the molten mixture is kept below themelting point of the drug. Preferably, at least 70 wt percent of thedrug remains crystalline within the molten feed, more preferably, atleast 80 wt percent and most preferably at least 90 wt percent.

The term “molten mixture” as used herein refers to a mixture of drug,glyceride (or other waxes), and any release modifying agents requiredheated sufficiently that the mixture becomes sufficiently fluid that themixture may be formed into droplets or atomized. Atomization of themolten mixture may be carried out using any of the atomization methodsdescribed below. Generally, the mixture is molten in the sense that itwill flow when subjected to one or more forces such as pressure, shear,and centrifugal force, such as that exerted by a centrifugal orspinning-disk atomizer. Thus, the drug/glyceride/release-modifying agentmixture may be considered “molten” when any portion of thedrug/glyceride/release-modifying agent mixture becomes sufficientlyfluid that the mixture, as a whole, may be atomized. Generally, amixture is sufficiently fluid for atomization when the viscosity of themolten mixture is less than about 20,000 cp. Often, the mixture becomesmolten when the mixture is heated above the melting point of theglyceride/release-modifying agent mixture, in cases where theglyceride/release-modifying agent mixture is sufficiently crystalline tohave a relatively sharp melting point; or, when theglyceride/release-modifying agent mixture is amorphous, above thesoftening point of the glyceride/release-modifying agent mixture. Themolten mixture is therefore often a suspension of solid particles in afluid matrix. In one preferred embodiment, the molten mixture comprisesa mixture of substantially crystalline drug particles suspended in aglyceride/release-modifying agent mixture that is substantially fluid.In such cases, a portion of the drug may be dissolved in theglyceride/release-modifying agent mixture and a portion of theglyceride/release-modifying agent mixture may remain solid.

Virtually any process may be used to form the molten mixture. One methodinvolves heating the glyceride/release-modifying agent mixture in a tankuntil it is fluid and then adding the drug to the moltenglyceride/release-modifying agent mixture. Generally, theglyceride/release-modifying agent mixture is heated to a temperature ofabout 10 degrees C. or more above the temperature at which it becomesfluid. When one or more of the glyceride/release-modifying agentcomponents is crystalline, this is generally about 10 degrees C. or moreabove the melting point of the lowest melting point material of themixture. The process is carried out so that at least a portion of thefeed remains fluid until atomized. Once the glyceride/release-modifyingagent mixture has become fluid, the drug may be added to the fluidcarrier or “melt.” Although the term “melt” generally refersspecifically to the transition of a crystalline material from itscrystalline to its liquid state, which occurs at its melting point, andthe term “molten” generally refers to such a crystalline material in itsfluid state, as used herein, the terms are used more broadly, referringin the case of “melt” to the heating of any material or mixture ofmaterials sufficiently that it becomes fluid in the sense that it may bepumped or atomized in a manner similar to a crystalline material in thefluid state. Likewise “molten” refers to any material or mixture ofmaterials that is in such a fluid state. Alternatively, the drug, theglyceride (or other wax), and the release-modifying agent may be addedto the tank and the mixture heated until the mixture has become fluid.

Once the glyceride/release-modifying agent mixture has become fluid andthe drug has been added, the molten mixture is mixed to ensure the drugis uniformly distributed therein. Mixing is generally done usingmechanical means, such as overhead mixers, magnetically driven mixersand stir bars, planetary mixers, and homogenizers. Optionally, thecontents of the tank can be pumped out of the tank and through anin-line, static mixer or extruder and then returned to the tank. Theamount of shear used to mix the molten feed should be sufficiently highto ensure uniform distribution of the drug in the molten carrier. Theamount of shear is kept low enough so the form of the drug does notchange, i.e., so as to cause an increase in the amount of amorphous drugor a change in the crystalline form of the drug. It is also preferredthat the shear not be so high as to reduce the particle size of the drugcrystals. The molten mixture can be mixed from a few minutes to severalhours, the mixing time being dependent on the viscosity of the feed andthe solubility of drug and any optional excipients in the carrier.

An alternative method of preparing the molten mixture is to use twotanks, melting either the glyceride (or other waxes) or therelease-modifying agent in one tank and the other component in anothertank. The drug is added to one of these tanks and mixed as describedabove. The two melts are then pumped through an in-line static mixer orextruder to produce a single molten mixture that is directed to theatomization process described below.

Another method that can be used to prepare the molten mixture is to usea continuously stirred tank system. In this system, the drug, glyceride(or other waxes), and release-modifying agent are continuously added toa heated tank equipped with means for continuous stirring, while themolten feed is continuously removed from the tank. The contents of thetank are heated such that the temperature of the contents is about 10degrees C. or more above the melting point of the carrier. The drug,glyceride (or other waxes), and release-modifying agent are added insuch proportions that the molten mixture removed from the tank has thedesired composition. The drug is typically added in solid form and maybe pre-heated prior to addition to the tank. The glyceride (or otherwaxes), and release-modifying agent may also be preheated or evenpre-melted prior to addition to the continuously stirred tank system.

In another method for forming the molten mixture is by an extruder. By“extruder” is meant a device or collection of devices that creates amolten extrudate by heat and/or shear forces and/or produces a uniformlymixed extrudate from a solid and/or liquid (e.g., molten) feed. Suchdevices include, but are not limited to single-screw extruders;twin-screw extruders, including co-rotating, counter-rotating,intermeshing, and non-intermeshing extruders; multiple screw extruders;ram extruders, consisting of a heated cylinder and a piston forextruding the molten feed; gear-pump extruders, consisting of a heatedgear pump, generally counter-rotating, that simultaneously heats andpumps the molten feed; and conveyer extruders. Conveyer extruderscomprise a conveyer means for transporting solid and/or powdered feeds,such, such as a screw conveyer or pneumatic conveyer, and a pump.

At least a portion of the conveyer means is heated to a sufficientlyhigh temperature to produce the molten mixture. The molten mixture mayoptionally be directed to an accumulation tank, before being directed toa pump, which directs the molten mixture to an atomizer. Optionally, anin-line mixer may be used before or after the pump to ensure the moltenmixture is substantially homogeneous. In each of these extruders themolten mixture is mixed to form a uniformly mixed extrudate. Such mixingmay be accomplished by various mechanical and processing means,including mixing elements, kneading elements, and shear mixing bybackflow. Thus, in such devices, the composition is fed to the extruder,which produces a molten mixture that can be directed to the atomizer.

In one embodiment, the composition is fed to the extruder in the form ofa solid powder. The powdered feed can be prepared using methods wellknown in the art for obtaining powdered mixtures with high contentuniformity. Generally, it is desirable that the particle sizes of thedrug, glyceride (or other waxes), and release-modifying agent be similarto obtain a substantially uniform blend. However, this is not essentialto the successful practice of the invention.

An example of a process for preparing a substantially uniform blend isas follows. First, the glyceride (or other waxes) and release-modifyingagent are milled so that their particle sizes are about the same as thatof the drug; next, the drug, glyceride (or other waxes), andrelease-modifying agent are blended in a V-blender for 20 minutes; theresulting blend is then de-lumped to remove large particles; theresulting blend is finally blended for an additional 4 minutes. In somecases it is difficult to mill the glyceride (or other waxes), andrelease-modifying agent to the desired particle size since many of thesematerials tend to be waxy substances and the heat generated during themilling process can gum up the milling equipment. In such cases, smallparticles of the glyceride (or other waxes), and release-modifying agentcan be formed using a melt- or spray-congeal process, as describedbelow. The resulting congealed particles of glyceride (or other waxes),and release-modifying agent can then be blended with the drug to producethe feed for the extruder.

Another method for producing the feed to the extruder is to melt theglyceride (or other waxes) and release-modifying agent in a tank, mix inthe drug as described above for the tank system, and then cool themolten mixture, producing a solidified mixture of drug and carrier. Thissolidified mixture can then be milled to a uniform particle size and fedto the extruder.

A two-feed extruder system can also be used to produce the moltenmixture. In this system the drug, glyceride (or other waxes) andrelease-modifying agent, all in powdered form, are fed to the extruderthrough the same or different feed ports. In this way, the need forblending the components is eliminated.

Alternatively, the glyceride (or other waxes) and release-modifyingagent in powder form may be fed to the extruder at one point, allowingthe extruder to melt the glyceride (or other waxes) andrelease-modifying agent. The drug is then added to the molten glyceride(or other waxes) and release-modifying agent through a second feeddelivery port part way along the length of the extruder, thus minimizingthe contact time of the drug with the molten glyceride (or other waxes)and release-modifying agent. The closer the second feed delivery port isto the extruder exit, the lower is the residence time of drug in theextruder. Multiple-feed extruders can be used when optional excipientsare included in the multiparticulate.

In another method, the composition is in the form of large solidparticles or a solid mass, rather than a powder, when fed to theextruder. For example, a solidified mixture can be prepared as describedabove and then molded to fit into the cylinder of a ram extruder andused directly without milling.

In another method, the glyceride (or other waxes) and release-modifyingagent can be first melted in, for example, a tank, and fed to theextruder in molten form. The drug, typically in powdered form, may thenbe introduced to the extruder through the same or a different deliveryport used to feed the glyceride (or other waxes) and release-modifyingagent into the extruder. This system has the advantage of separating themelting step for the glyceride (or other waxes) and release-modifyingagent from the mixing step, minimizing contact of the drug with themolten glyceride (or other waxes) and release-modifying agent.

In each of the above methods, the extruder should be designed such thatit produces a molten mixture with the drug crystals uniformlydistributed in the glyceride/release-modifying agent mixture. Generally,the temperature of the extrudate should be about 10 degrees C. or moreabove the temperature at which the drug and carrier mixture becomesfluid. The various zones in the extruder should be heated to appropriatetemperatures to obtain the desired extrudate temperature as well as thedesired degree of mixing or shear, using procedures well known in theart. As discussed above for mechanical mixing, a minimum shear should beused to produce a uniform molten mixture, such that the crystalline formof the drug is unchanged and that dissolution or formation of amorphousdrug is minimized.

The feed is preferably molten prior to congealing for at least 5seconds, more preferably at least 10 seconds, and most preferably atleast 15 seconds, so as to ensure adequate homogeneity of thedrug/glyceride/release-modifying agent melt. It is also preferred thatthe molten mixture remain molten for no more than about 20 minutes tolimit exposure of the drug to the molten mixture. As described above,depending on the reactivity of the chosen glyceride/release-modifyingagent mixture, it may be preferable to further reduce the time that themixture is molten to well below 20 minutes in order to limit drugdegradation to an acceptable level. In such cases, such mixtures may bemaintained in the molten state for less than 15 minutes, and in somecases, even less than 10 minutes. When an extruder is used to producethe molten feed, the times above refer to the mean time from whenmaterial is introduced to the extruder to when the molten mixture iscongealed. Such mean times can be determined by procedures well known inthe art. In one exemplary method, a small amount of dye or other similarcompound is added to the feed while the extruder is operating undernominal conditions. Congealed multiparticulates are then collected overtime and analyzed for the dye, from which the mean time is determined.

Once the molten mixture has been formed, it is delivered to an atomizerthat breaks the molten feed into small droplets. Virtually any methodcan be used to deliver the molten mixture to the atomizer, including theuse of pumps and various types of pneumatic devices (e.g., pressurizedvessels, piston pots). When an extruder is used to form the moltenmixture, the extruder itself can be used to deliver the molten mixtureto the atomizer. Typically, the molten mixture is maintained at anelevated temperature while delivering the mixture to the atomizer toprevent solidification of the mixture and to keep the molten mixtureflowing.

Generally, atomization occurs in one of several ways, including (1) by“pressure” or single-fluid nozzles; (2) by two-fluid nozzles; (3) bycentrifugal or spinning-disk atomizers, (4) by ultrasonic nozzles; and(5) by mechanical vibrating nozzles. Detailed descriptions ofatomization processes can be found in Lefebvre, Atomization and Sprays(1989) or in Perry's Chemical Engineers' Handbook (7th Ed. 1997).Preferably, a centrifugal or spinning-disk atomizer is used, such as theFX1 100-mm rotary atomizer manufactured by Niro A/S (Soeborg, Denmark).

Once the molten mixture has been atomized, the droplets are congealed,typically by contact with a gas or liquid at a temperature below thesolidification temperature of the droplets. Typically, it is desirablethat the droplets are congealed in less than about 60 seconds,preferably in less than about 10 seconds, more preferably in less thanabout 1 second. Often, congealing at ambient temperature results insufficiently rapid solidification of the droplets. However, thecongealing step often occurs in an enclosed space to simplify collectionof the multiparticulates. In such cases, the temperature of thecongealing media (either gas or liquid) will increase over time as thedroplets are introduced into the enclosed space, potentially effectingthe formation of the multiparticulates or the chemical stability of thedrug. Thus, a cooling gas or liquid is often circulated through theenclosed space to maintain a constant congealing temperature. When it isdesirable to minimize the time the drug is exposed to high temperatures,e.g., to prevent degradation, the cooling gas or liquid can be cooled tobelow ambient temperature to promote rapid congealing, thus minimizingformation of degradants.

Following formation of the multiparticulates, it may be desired topost-treat the multiparticulates to improve drug crystallinity and/orthe stability of the multiparticulate.

The multiparticulates may also be mixed or blended with one or morepharmaceutically acceptable materials to form a suitable dosage form.Suitable dosage forms include tablets, capsules, sachets, oral powdersfor constitution, and the like.

Following formation of the melt spray congeal multiparticulates, themultiparticulates may optionally be coated with an additional exteriorcoating. The exterior coating may be any conventional coating, such as aprotective film coating, a coating to provide delayed or sustainedrelease of the drug, or to provide tastemasking.

In one embodiment, the coating is an enteric coating to provide delayedrelease of the drug. By “enteric coating” is meant an acid resistantcoating that remains intact and does not dissolve at pH of less thanabout 4. The enteric coating surrounds the multiparticulate so that thesolid amorphous dispersion layer does not dissolve or erode in thestomach. The enteric coating may include an enteric coating polymer.Enteric coating polymers are generally polyacids having a pK_(a) ofabout 3 to 5. Examples of enteric coating polymers include: cellulosederivatives, such as cellulose acetate phthalate, cellulose acetatetrimellitate, hydroxypropyl methyl cellulose acetate succinate,cellulose acetate succinate, carboxy methyl ethyl cellulose,methylcellulose phthalate, and ethylhydroxy cellulose phthalate; vinylpolymers, such as polyvinyl acetate phthalate, vinyl acetate-maleicanhydride copolymer; polyacrylates; and polymethacrylates such as methylacrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octylacrylate copolymer; and styrene-maleic mono-ester copolymer. These maybe used either alone or in combination, or together with other polymersthan those mentioned above.

One class of enteric coating materials are the pharmaceuticallyacceptable methacrylic acid copolymer which are copolymers, anionic incharacter, based on methacrylic acid and methyl methacrylate. Some ofthese polymers are known and sold as enteric polymers, for examplehaving a solubility in aqueous media at pH 5.5 and above, such as thecommercially available EUDRAGIT enteric polymers, such as Eudragit L 30,a polymer synthesized from dimethylaminoethyl methacrylate and EudragitS and Eudragit FS.

The exterior coatings may include conventional plasticizers, includingdibutyl phthalate; dibutyl sebacate; diethyl phthalate; dimethylphthalate; triethyl citrate; benzyl benzoate; butyl and glycol esters offatty acids; mineral oil; oleic acid; stearic acid; cetyl alcohol;stearyl alcohol; castor oil; corn oil; coconut oil; and camphor oil; andother excipients such as anti-tack agents, glidants, etc. Forplasticizers, triethyl citrate, coconut oil and dibutyl sebacate areparticularly preferred.

Exterior coatings can be formed using solvent-based and hot-melt coatingprocesses. In solvent-based processes, the coating is made by firstforming a solution or suspension comprising the solvent, the coatingmaterial and optional coating additives. The coating materials may becompletely dissolved in the coating solvent, or only dispersed in thesolvent as an emulsion or suspension or a combination of the two. Latexdispersions are an example of an emulsion or suspension that may beuseful as in a solvent-based coating process. In one aspect, the solventis a liquid at room temperature.

Coating may be conducted by conventional techniques, such as by pancoaters, rotary granulators and fluidized bed coaters such as top-spray,tangential-spray or bottom-spray (Wurster coating). A top-spray methodcan also be used to apply the coating. In this method, coating solutionis sprayed down onto the fluidized cores. The solvent evaporates fromthe coated cores and the coated cores are re-fluidized in the apparatus.Coating continues until the desired coating thickness is achieved.Compositions and methods for making the multiparticulates of thisembodiment are detailed in the following US Patent Applications, US2005-0181062, US 2005-0181062, US 2008-0199527, US 2005-0186285A1 whichare herein incorporated as reference in their entirety.

The multiparticulates of the invention generally are of a mean diameterfrom about 40 to about 3,000 micron, with a preferred range of 50 to1,000 micron, and most preferably from about 100 to 300 micron. Whilethe multiparticulates can have any shape and texture, it is preferredthat they be spherical, with a smooth surface texture. These physicalcharacteristics of the multiparticulates improve their flow properties,permit them to be uniformly coated (if desired). As used herein, theterm “about” means+/−10% of the value.

The multiparticulates of the present invention are particularly suitablefor controlled release or delayed release or any combination of thesetwo release profiles when introduced to a use environment. As usedherein, a “use environment” can be either the in vivo environment of thegastrointestinal (GI) tract or the in vitro dissolution tests describedherein. Information about in vivo release rates can be determined fromthe pharmacokinetic profile using standard deconvolution orWagner-Nelson treatment of the data which should be readily known tothose skilled in the art.

Once the tofacitinib matrix multiparticulates are formed through methodsdescribed above, they may be blended with compressible excipients suchas lactose, microcrystalline cellulose, dicalcium phosphate, and thelike and the blend compressed to form a tablet or capsule. Disintegrantssuch as sodium starch glycolate or crosslinked poly(vinyl pyrrolidone)are also usefully employed. Tablets or capsules prepared by this methoddisintegrate when placed in an aqueous medium (such as the GI tract),thereby exposing the multiparticulate matrix which releases tofacitinibthere from.

Other conventional formulation excipients may be employed in thecontrolled release portion of the invention, including those excipientswell known in the art, e.g., as described in Remington: The Science andPractice of Pharmacy, 20^(th) edition (2000). Generally, excipients suchas surfactants, pH modifiers, fillers, matrix materials, complexingagents, solubilizers, pigments, lubricants, glidants, flavorants, and soforth may be used for customary purposes and in typical amounts withoutadversely affecting the properties of the compositions.

Example matrix materials, fillers, or diluents include lactose,mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar,microcrystalline cellulose, powdered cellulose, starch, pregelatinizedstarch, dextrates, dextran, dextrin, dextrose, maltodextrin, calciumcarbonate, dibasic calcium phosphate, tribasic calcium phosphate,calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers,polyethylene oxide, hydroxypropyl methyl cellulose and mixtures thereof.

Sustained Release—Osmotic Systems

In another embodiment, tofacitinib is incorporated into osmotic deliverydevices or “osmotic pumps” as they are known in the art. Osmotic pumpscomprise a core containing an osmotically effective compositionsurrounded by a semipermeable membrane. The term “semipermeable” in thiscontext means that water can readily diffuse through the membrane, butsolutes dissolved in water typically cannot readily diffuse through themembrane relative to the rate of water diffusion through the membrane.In use, when placed in an aqueous environment, the device imbibes waterdue to the osmotic activity of the core composition. Owing to thesemipermeable nature of the surrounding membrane, the contents of thedevice (including tofacitinib and any excipients) cannot pass throughthe non-porous regions of the membrane and are driven by osmoticpressure to leave the device through an opening or passagewaypre-manufactured into the dosage form or, alternatively, formed in situin the GI tract as by the bursting of intentionally-incorporated weakpoints in the coating under the influence of osmotic pressure. Theosmotically effective composition includes water-soluble species, whichgenerate a colloidal osmotic pressure, and water-swellable polymers.Examples of such dosage forms are well known in the art. See, forexample, Remington: The Science and Practice of Pharmacy, 21^(st)Edition, 2006 Chapter 47; page 950-1 and herein incorporated asreference.

In one embodiment of the present invention, tofacitinib is incorporatedinto a bilayer osmotic delivery device such that thetofacitinib-containing composition must include an entraining agent inthe form of a water-swellable polymer and a second push layer or waterswelling layer which contains water-swellable polymers and/orosmoticallly active agents, but does not contain any active agent. Thebilayer tablet or capsule is surrounded by a semi-permeable membranewhich contains one or more openings which are manufactured into thedosage form through such techniques as laser drilling. Suchwater-swellable polymers are often referred to in the pharmaceuticalarts as an “osmopolymer” or a “hydrogel.” The entraining agent suspendsor entrains the drug so as to aid in the delivery of the drug throughthe delivery port(s). While not wishing to be bound by any particulartheory, it is believed that upon the imbibition of water into the dosageform, the entraining agent has enough viscosity to allow it to suspendor entrain the drug, while at the same time remaining sufficiently fluidto allow the entraining agent to pass through the delivery port(s) alongwith the drug. The amount of the entraining agent present in thetofacitinib-containing composition may range from about 20 wt % to about95 wt %. The entraining agent may be a single material or a mixture ofmaterials. Non-crosslinked polyethylene oxide (PEO) may be used as theentraining agent. Other suitable entraining agents include hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methylcellulose(MC), hydroxyethyl cellulose (HEC) and polyvinyl pyrrolidone (PVP), aswell as mixtures of these polymers with PEO.

The choice of the molecular weight for the PEO depends in part onwhether the PEO makes up the bulk of the non-tofacitinib portion of thetofacitinib-containing composition, or whether significant amounts ofother low-molecular weight water-soluble excipients are included; thatis, the PEO molecular weight choice depends on the fraction of thetofacitinib-containing composition that is PEO. Should thetofacitinib-containing composition not become fluid rapidly, the dosageform can swell and rupture the coating that surrounds the core,potentially causing failure of the dosage form. Where the excipients ofthe tofacitinib-containing composition are primarily PEO (e.g., PEOmakes up about 60 wt % or more of the non-tofacitinib components of thetofacitinib-containing composition), it is generally preferred that thePEO have an average molecular weight of from about 100,000 to 300,000daltons. (As used herein, reference to molecular weights of polymersshould be taken to mean average molecular weights.)

Alternatively, another embodiment of the present invention uses a highermolecular weight of PEO from about 500,000 to 800,000 daltons at a lowerfraction of the non-tofacitinib excipients, a portion of the PEO beingreplaced with a fluidizing agent. Ordinarily, when PEO makes up about 60wt % or more of the non-tofacitinib components of thetofacitinib-containing composition, PEO having a molecular weight of500,000 daltons or more makes the tofacitinib-containing composition tooviscous, and can result in a rupture of the coating or at least in adelay of the release of tofacitinib. However, it has been found thatsuch higher molecular weight PEO is preferred when the non-tofacitinibcomponents of the tofacitinib-containing composition comprise less thanabout 60 wt % PEO and also contain a fluidizing agent. When using ahigher molecular weight PEO, the amount of fluidizing agent present inthe tofacitinib-containing composition may range from about 5 to about50 wt %, preferably 10 to 30 wt % of the tofacitinib-containingcomposition. Preferred fluidizing agents are low molecular weight,water-soluble solutes such as non-reducing sugars and organic acids withaqueous solubilities of 30 mg/mL or greater. Suitable sugars includexylitol, mannitol, sorbitol, and maltitol. Salts useful as a fluidizingagent include sodium chloride, sodium lactate and sodium acetate.Organic acids useful as a fluidizing agent include adipic acid, citricacid, malic acid, fumaric acid, succinic acid and tartaric acid.

The presence of the fluidizing agent, along with a relatively low levelof higher molecular weight PEO (e.g., about 500,000 to about 800,000daltons) allows the tofacitinib-containing composition to rapidly reacha low viscosity upon imbibition of water. In addition, it has been foundthat such an embodiment is capable of delivering relatively high amountsof tofacitinib.

The tofacitinib-containing composition may also contain otherwater-swellable polymers. For example, the tofacitinib-containingcomposition may contain relatively small amounts of water-swellablepolymers that greatly expand in the presence of water. Suchwater-swellable polymers include sodium starch glycolate, sold under thetrade name EXPLOTAB, and croscarmelose sodium, sold under the trade nameAC-DI-SOL. Such polymers may be present in amounts ranging from 0 wt %to 10 wt % of the tofacitinib-containing composition.

The tofacitinib-containing composition may optionally includeosmotically effective solutes, often referred to as “osmogens” or“osmagents.” The amount of osmagent present in thetofacitinib-containing composition may range from about 0 wt % to about50 wt %, preferably 10 wt % to 30 wt % of the tofacitinib-containingcomposition. Typical classes of suitable osmagents are water-solublesalts, sugars, organic acids, and other low-molecule-weight organiccompounds that are capable of imbibing water to thereby establish anosmotic pressure gradient across the barrier of the surrounding coating.Typical useful salts include magnesium sulfate, magnesium chloride,calcium chloride, sodium chloride, lithium chloride, potassium sulfate,sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride,and sodium sulfate. Conventionally, chloride salts such as sodiumchloride are utilized as osmagents.

The tofacitinib-containing composition may further includesolubility-enhancing agents or solubilizers that promote the aqueoussolubility of the drug, present in an amount ranging from about 0 toabout 30 wt % of the tofacitinib-containing composition. Solubilizersuseful with tofacitinib include organic acids and organic acid salts,partial glycerides, e.g., less than fully esterified derivatives ofglycerin, including glycerides, monoglycerides, diglycerides, glyceridederivatives, polyethylene glycol esters, polypropylene glycol esters,polyhydric alcohol esters, polyoxyethylene ethers, sorbitan esters,polyoxyethylene sorbitan esters, and carbonate salts.

A preferred class of solubilizers is organic acids. Since tofacitinib isa base which is solubilized by protonation, and since its solubility inan aqueous environment of pH 5 or higher is reduced, it is believed thataddition of an organic acid to the Tofacitinib-containing compositionassists in solubilization and hence absorption of tofacitinib. Even aslight decrease in the pH of the aqueous solution at high pH results indramatic increases in the solubility of tofacitinib. Organic acids canalso promote stability during storage prior to introduction to a useenvironment due to their tendency to maintain tofacitinib in aprotonated state.

There are a variety of factors to consider when choosing an appropriateorganic acid for use as a solubilizer with tofacitinib in an osmoticdosage form. The acid should not interact adversely with tofacitinib,should have appropriate water solubility, and should provide goodmanufacturing properties.

Accordingly, it has been found that a preferred subset of organic acidsmeeting such criteria consists of citric, succinic, fumaric, adipic,malic and tartaric acids. Citric, malic, and tartaric acid have theadvantage of high water solubility and high osmotic pressure. Succinicand fumaric acid offer a combination of both moderate solubility andmoderate osmotic pressure.

The water-swellable composition may also optionally contain a colorant.The purpose of the colorant is to allow identification of thedrug-containing side of the tablet face for purposes of providing thedelivery port, such as by laser drilling through the coating. Acceptablecolorants include, but are not limited to, Red Lake No. 40, FD C Blue 2and FD C Yellow 6.

The tofacitinib-containing layer and/or the water-swellable compositionlayer and/or the functional rate controlling membrane may optionallycontain an antioxidant, such as but not limited to BHT, BHA, sodiummetabisulfite, propyl galate, glycerin, vitamin E, Citric Acid orascorbyl palmitate. The antioxidant may be present in an amount rangingfrom 0 to 10 wt % of the tofacitinib-containing composition layer and/orthe water-swellable composition layer and/or the functional ratecontrolling membrane. For additional examples of antioxidants, see C.-M.Andersson, A. Hallberg, and T. Hoegberg. Advances in the development ofpharmaceutical antioxidants. Advances in Drug Research. 28:65-180, 1996.

Water-swellable composition may also include other conventionalpharmaceutically useful excipients such as a binder, including HPC,HPMC, HEC, MC, and PVP, a tableting aid, such as microcrystallinecellulose, and a lubricant such as magnesium stearate.

The water-swellable composition is prepared by mixing thewater-swellable polymer and the other excipients to form a uniformblend. To obtain a uniform blend, it is desirable to either wet or drygranulate or dry blend ingredients that have similar particle sizesusing the types of processes known to those skilled in the art.

Tableting

The core is prepared by first placing a mixture of thetofacitinib-containing composition into a tablet press and then levelingthe mixture by gentle compression. The water-swellable composition isthen placed on top of the tofacitinib-containing composition andcompressed in order to complete formation of the core. Alternatively,the water-swellable composition can be placed into the tablet pressfirst, followed by the tofacitinib-containing composition.

The respective amounts of tofacitinib-containing composition andwater-swellable composition are chosen to provide satisfactorytofacitinib release. When it is desired to provide a large tofacitinibdose in a relatively small dosage size, it is desired to maximize theamount of tofacitinib-containing composition and minimize the amount ofwater-swellable composition, while still obtaining good releaseperformance. In the dosage forms of the present invention, when thewater-swellable polymer in the water-swellable composition is only PEO,the tofacitinib-containing composition may comprise from about 50 toabout 85 wt % of the core, and preferably from about 60 to about 70 wt%. These values correspond to a weight ratio of thetofacitinib-containing composition to water-swellable composition of 1to about 5.7. When all or part of the water-swellable polymer in thewater-swellable composition comprises sodium starch glycolate orcroscarmellose sodium, the tofacitinib-containing composition maycomprise from 50 to 90 wt % of the core, and preferably from about 75 toabout 85 wt %. Those values correspond to the weight ratio of thetofacitinib-containing composition to water-swellable composition offrom 1 to 9. The absolute value of the diameter and height of thetablets of the present invention can vary over a wide range.

The Coating

Following formation of the core, the semi-permeable coating is applied.The coating should have high water permeability and a high strength,while at the same time be easily fabricated and applied. High waterpermeability is required to permit water to enter the core in sufficientvolume. High strength is required to ensure the coating does not burstwhen the core swells as it imbibes water, leading to an uncontrolleddelivery of the core contents. Finally, the coating must have highreproducibility and yield.

It is essential that the coating have at least one delivery port incommunication with the interior and exterior of the coating for deliveryof the tofacitinib-containing composition. Furthermore, the coating mustbe non-dissolving and non-eroding during release of thetofacitinib-containing composition, generally meaning that it bewater-insoluble, such that tofacitinib is substantially entirelydelivered through the delivery port(s), in contrast to delivery viapermeation through the coating.

Coatings with these characteristics can be obtained using hydrophilicpolymers such as plasticized and unplasticized cellulose esters, ethers,and ester-ethers. Particularly suitable polymers include celluloseacetate (CA), cellulose acetate butyrate (CAB), and ethyl cellulose(EC). One set of polymers are cellulose acetates having acetyl contentsof 25 to 42%. One typical polymer is CA having an acetyl content of39.8%, specifically, CA 398-10 (Eastman Fine Chemicals, Kingsport,Tenn.). CA 398-10 is reported to have an average molecular weight ofabout 40,000 daltons. Another typical CA having an acetyl content of39.8% is high molecular weight CA having an average molecular weightgreater than about 45,000, and specifically, CA 398-30 (Eastman FineChemical) which is reported to have an average molecular weight of50,000 daltons.

Coating is conducted in conventional fashion by first forming a coatingsolution and then coating by dipping, fluidized bed coating, or by pancoating. To accomplish this, a coating solution is formed comprising thepolymer and a solvent. Typical solvents useful with the cellulosicpolymers above include acetone, methyl acetate, ethyl acetate, isopropylacetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone,ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate,methylene dichloride, ethylene dichloride, propylene dichloride,nitroethane, nitropropane, tetrachloroethane, 1,4-dioxane,tetrahydrofuran, diglyme, and mixtures thereof. The coating solutiontypically contains 2 to 15 wt % of the polymer.

The coating solution may also include pore-formers or non-solvents inany amount as long as the polymer remains soluble at the conditions usedto form the coating and as long as the coating remains water permeableand has sufficient strength. Pore-formers and their use in fabricatingcoatings are described in U.S. Pat. Nos. 5,698,220 and 5,612,059, thepertinent disclosures of which are incorporated herein by reference. Theterm “pore former,” as used herein, refers to a material added to thecoating solution that has low or no volatility relative to the solventsuch that it remains as part of the coating following the coatingprocess but that is sufficiently water swellable or water soluble suchthat, in the aqueous use environment it provides a water-filled orwater-swollen channel or “pore” to allow the passage of water, therebyenhancing the water permeability of the coating. Suitable pore formersinclude but are not limited to hydroxypropylcellulose (HPC),polyethylene glycol (“PEG”), PVP, and PEO. To obtain a combination ofhigh water permeability and high strength when PEG or HPC are used as apore former, the weight ratio of CA:PEG or CA:HPC should range fromabout 6:4 to about 9:1.

The addition of a non-solvent such as water to the coating solutionresults in exceptional performance. By “non-solvent” is meant anymaterial added to the coating solution that substantially dissolves inthe coating solution and reduces the solubility of the coating polymeror polymers in the solvent. In general, the function of the non-solventis to impart porosity to the resulting coating. As described below,porous coatings have higher water permeability than an equivalent weightof a coating of the same composition that is not porous and thisporosity is indicated by a reduction in the density of the coating(mass/volume). Although not wishing to be bound by any particularmechanism of pore formation, it is generally believed that addition of anon-solvent imparts porosity to the coating during evaporation ofsolvent by causing the coating solution to undergo liquid and liquidphase separation prior to solidification. The suitability and amount ofa particular candidate material can be evaluated for use as anon-solvent by progressively adding the candidate non-solvent to thecoating solution until it becomes cloudy. If this does not occur at anyaddition level up to about 50 wt % of the coating solution, it generallyis not appropriate for use as a non-solvent. When clouding is observed,termed the “cloud point,” an appropriate level of non-solvent formaximum porosity is the amount just below the cloud point. For acetonesolutions comprising 7 wt % CA and 3 wt % PEG, the cloud point is atabout 23 wt % water. When lower porosities are desired, the amount ofnon-solvent can be reduced as low as desired.

Suitable non-solvents are any materials that have appreciable solubilityin the solvent and that lower the coating polymer solubility in thesolvent. The preferred non-solvent depends on the solvent and thecoating polymer chosen. In the case of using a volatile polar coatingsolvent such as acetone, suitable non-solvents include water, glycerol,alcohols such as methanol or ethanol.

When using CA 398-10, coating solution weight ratios of CA:PEG3350:water are 2.4:1.6:5, 2.8:1.2:5, 3.2:0.8:5, and 3.6:0.4:5, with theremainder of the solution comprising a solvent such as acetone. Thus,for example, in a solution having a weight ratio of CA:PEG 3350:water of2.8:1.2:5, CA comprises 2.8 wt % of the solution, PEG 3350 comprises 1.2wt % of the solution, water comprises 5 wt % of the solution, andacetone comprises the remaining 91 wt %. Likewise, coating solutionweight ratios of CA:HPC:water are 1.2:0.8:9.8, 2.4:1.6:19.6,1.6:0.4:4.9, and 3.2:0.8:9.8, with the remainder of the solutioncomprising a solvent such as acetone. Thus, for example, in a solutionhaving a weight ratio of CA:HPC:water of 1.2:0.8:10, CA comprises 1.2 wt% of the solution, HPC comprises 0.8 wt % of the solution, watercomprises 10 wt % of the solution, and acetone comprises the remaining88 wt %. Further, coating solution weight ratios of CA:HPC:methanol are1.8:1.2:19.6, 2.4:1.6:19.6, 1.6:0.4:4.9, and 3.2:0.8:9.8, with theremainder of the solution comprising a solvent such as acetone. Thus,for example, in a solution having a weight ratio of CA:HPC:methanol of1.8:1.2:19.6, CA comprises 1.8 wt % of the solution, HPC comprises 1.2wt % of the solution, methanol comprises 19.6 wt % of the solution, andacetone comprises the remaining 77.4 wt %.

When incorporating antioxidants into the coating solution, a thirdsolvent may be required to ensure good dispersion of the antioxidantinto the coating. For example, a CA:PEG:water composition of 2.4:1.6:5that includes 0.05 wt % of antioxidant of the solution requires 5 wt %methanol and 86% acetone.

Coatings formed from these coating solutions are generally porous. By“porous” is meant that the coating in the dry state has a density lessthan the density of the same material in a nonporous form. By “nonporousform” is meant a coating material formed by using a coating solutioncontaining no non-solvent, or the minimal amount of non-solvent requiredto produce a homogeneous coating solution. The dry-state density of thecoating can be calculated by dividing the coating weight (determinedfrom the weight gain of the tablets before and after coating) by thecoating volume (calculated by multiplying the coating thickness, asdetermined by optical or scanning electron microscopy, by the tabletsurface area). The porosity of the coating is one of the factors thatleads to the combination of high water permeability and high strength ofthe coating.

The weight of the coating around the core depends on the composition andporosity of the coating, but generally should be present in an amountranging from 3 to 30 wt %, based on the weight of the uncoated core. Acoating weight of at least about 8 wt %, is typically preferred forsufficient strength for reliable performance, although lower coatingweights can be used to achieve desire high water imbibing rates and,subsequently, higher release rates of tofacitinib from the dosage form.

While porous coatings based on CA, PEG or HPC, and water described abovetranslate to excellent results, other pharmaceutically acceptablematerials could be used in the coating so long as the coating has therequisite combination of high water permeability, high strength, andease of fabrication and application. Further, such coatings may bedense, porous, or “asymmetric,” having one or more dense layers and oneor more porous layers such as those disclosed in U.S. Pat. Nos.5,612,059 and 5,698,220, the pertinent disclosures of which areincorporated herein by reference.

The coating must also contain at least one delivery port incommunication with the interior and exterior of the coating to allow forrelease of the drug-containing composition to the exterior of the dosageform. The delivery port can range in size from about the size of thedrug particles, and thus could be as small as 1 to 100 microns indiameter and may be termed pores, up to about 5000 microns in diameter.The shape of the port may be substantially circular, in the form of aslit, or other convenient shape to ease manufacturing and processing.The port(s) may be formed by post-coating mechanical or thermal means orwith a beam of light (e.g., a laser), a beam of particles, or otherhigh-energy source, or may be formed in situ by rupture of a smallportion of the coating. Such rupture may be controlled by intentionallyincorporating a relatively small weak portion into the coating. Deliveryports may also be formed in situ by erosion of a plug of water-solublematerial or by rupture of a thinner portion of the coating over anindentation in the core. Delivery ports may be formed by coating thecore such that one or more small regions remain uncoated. In addition,the delivery port can be a large number of holes or pores that may beformed during coating, as in the case of asymmetric membrane coatings,described in more detail herein, and of the type disclosed in U.S. Pat.Nos. 5,612,059 and 5,698,220, the disclosures of which are incorporatedby reference. When the delivery pathways are pores there can be amultitude of such pores that range in size from 1 micron to greater than100 microns. During operation, one or more of such pores may enlargeunder the influence of the hydrostatic pressure generated duringoperation. At least one delivery port should be formed on the side ofcoating that is adjacent to the tofacitinib-containing composition, sothat the tofacitinib-containing composition will be extruded out of thedelivery port by the swelling action of the water-swellable composition.It is recognized that some processes for forming delivery ports may alsoform holes or pores in the coating adjacent to the water-swellablecomposition.

The coating may optionally include a port in communication with thewater-swellable composition. Such a delivery port does not typicallyalter the tofacitinib release characteristics of the dosage form, butmay provide manufacturing advantages. It is believed that thewater-swellable compositions, such as those containing PEO with amolecular weight between 3,000,000 and 8,000,000 daltons, are tooviscous to appreciably exit the port. In dosage forms wherein thedelivery ports are drilled either mechanically or by laser, the tabletmust be oriented so that at least one delivery port is formed in thecoating adjacent to the tofacitinib-containing composition. A colorantwithin the water-swellable composition is used to orient the core dosageform during the drilling step in manufacture. By providing a deliveryport on both faces of the dosage form, the need to orient the dosageform may be eliminated and the colorant may be removed from thewater-swellable composition.

In yet another embodiment, tofacitinib is incorporated into a variationof the above disclosed osmotic delivery device, an asymmetric membranetechnology (AMT). These devices have been disclosed in Herbig, et al.,J. Controlled Release, 35, 1995, 127-136, and U.S. Pat. Nos. 5,612,059and 5,698,220 as coatings in osmotic drug delivery systems. These AMTsystems provide the general advantages of osmotic controlled releasedevices (reliable drug delivery independent of position ingastrointestinal tract), yet do not require the added manufacturing stepof drilling a hole in the coating, as seen with a number of otherosmotic systems. In the formation of these porous coatings, awater-insoluble polymer is combined with a water-soluble, pore-formingmaterial. The mixture is coated onto an osmotic tablet core from acombination of water and solvent. As the coating dries, a phaseinversion process occurs whereby a porous, asymmetric membrane isproduced. The use of an AMT system for controlled release of a drug withsimilar physiochemical properties is described in US Patent ApplicationPublication US2007/0248671 and herein incorporated as reference.

While a number of materials have been disclosed for use as pore-formersin the production of asymmetric membranes, the previously disclosedmaterials all bring chemical or physical stability issues into thesystem. In particular, many of the prior art materials are liquids,which can potentially migrate out of the coating during storage. Of theones that are solid, both polymeric materials and inorganic materialshave been taught. Inorganic materials can be difficult to use for anumber of reasons. In particular, they often have a tendency tocrystallize and/or adsorb moisture on storage. The particular polymericmaterials that have been taught include polyvinylpyrrolidone (PVP) andpolyethylene glycol (PEG) derivatives. Both of these materials have astrong tendency to form peroxides and/or formaldehyde upon storage (seefor example Waterman, et al., “Impurities in Drug Products” in Handbookof Isolation and Characterization of Impurities in Pharmaceuticals, S.Ajira and K. M. Alsante, Eds. 2003, pp. 75-85). Many drug substances arereactive with such polymer degradation products, both because of theirintrinsic reactivity and their tendency to migrate upon storage.However, this formulation space is relatively narrow. U.S. Pat. No.4,519,801 discloses a wide list of water-soluble polymeric componentsuseful for coatings in osmotic systems, but fails to teach appropriateselections of water-soluble components for AMT systems. There remains,therefore, a need for new pore-forming materials for AMT systems whereinthe pore-forming materials do not generate reactive byproducts,crystallize or migrate from the coating upon storage.

One aspect of the present invention provides a dosage form whichcomprises (a) a core containing at least one pharmaceutically activeingredient and (b) at least one asymmetric membrane technology coatingwherein said coating comprises:

a. one or more substantially water-insoluble polymers, and

b. one or more solid, water-soluble polymeric materials that do notcontain amounts of hydrogen peroxide or formaldehyde greater than about0.01 percent w:w after storage at 40 degrees C./75 percent RH for 12weeks.

One aspect of the present invention also provides a dosage form whereinthe dosage form delivers drug primarily by osmotic pressure. Inparticular embodiments, the present invention provides a dosage formwherein the pharmaceutically active ingredient is tofacitinib or apharmaceutically acceptable salt thereof. The water-insoluble polymer asused in the present invention preferably comprises a cellulosederivative, more preferably, cellulose acetate. The solid, water-solublepolymeric material as used in the present invention comprises a polymerhaving a weight average molecular weight between 2000 and 50,000daltons. In preferable embodiments, the solid, water-soluble polymericmaterial is selected from the group consisting of water-solublecellulose derivatives, acacia, dextrin, guar gum, maltodextrin, sodiumalginate, starch, polyacrylates, polyvinyl alcohols and zein. Inparticular embodiments, the water-soluble cellulose derivatives comprisehydroxypropylcellulose, hydroxypropylmethylcellulose andhydroxyethylcellulose. In certain embodiments, the solid, water-soluble,polymeric material has a viscosity for a 5 percent w:w aqueous solutionof less than 400 mPa s. In certain other embodiments, the solid,water-soluble, polymeric material has a viscosity for a 5 percent w:waqueous solution of less than 300 mPa s. In other embodiments, thesolid, water-soluble, polymeric material has a softening temperaturegreater than 55 degrees C.

The dosage form of the present invention may be a tablet or amultiparticulate. In certain embodiments, the core of the presentinvention contains a sugar. More preferably, the sugar is sorbitol. Incertain embodiments, the water-insoluble polymer is cellulose acetateand said solid, water-soluble polymeric material ishydroxypropylcellulose. In certain preferred embodiments, the dosageform of the invention contains tofacitinib, or a pharmaceuticallyacceptable salt thereof, as the pharmaceutically active ingredient,while the water-insoluble polymer is cellulose acetate and the solid,water-soluble polymeric material is hydroxypropylcellulose.

A process of the present invention encompasses the process wherein thecoating is applied from a mixture of acetone and water using a pancoating. The process of the present invention also encompasses theprocess wherein the asymmetric membrane comprises cellulose acetate andhydroxypropylcellulose which is coated from a mixture of acetone towater between about 9:1 and 6:4, w:w, and more preferably between about7:3 and about 6:4, w:w, using a pan coater. In particular, the processof the present invention encompasses the process wherein the corecomprises tofacitinib, or a pharmaceutically acceptable salt thereof.

In the preparation of the asymmetric membrane coatings of the presentinvention, the water-insoluble component of the asymmetric membranecoating preferentially is formed from cellulose derivatives. Inparticular, these derivatives include cellulose esters and ethers,namely the mono-, di- and triacyl esters wherein the acyl group consistsof two to four carbon atoms and lower alkyl ethers of cellulose whereinthe alkyl group has one to four carbon atoms. The cellulose esters canalso be mixed esters, such as cellulose acetate butyrate, or a blend ofcellulose esters. The same variations can be found in ethers ofcellulose and include blends of cellulose esters and cellulose ethers.Other cellulose derivatives which can be used in making asymmetricmembranes of the present invention include cellulose nitrate,acetaldehyde dimethyl cellulose, cellulose acetate ethyl carbamate,cellulose acetate phthalate, cellulose acetate methyl carbamate,cellulose acetate succinate, cellulose acetate dimethaminoacetate,cellulose acetate ethyl carbonate, cellulose acetate dimethaminoacetate,cellulose acetate ethyl carbonate, cellulose acetate chloroacetate,cellulose acetate ethyl oxalate, cellulose acetate methyl sulfonate,cellulose acetate butyl sulfonate, cellulose acetate p-toluenesulfonate, cellulose cyanoacetates, cellulose acetate trimellitate,cellulose methacrylates and hydroxypropylmethylcellulose acetatesuccinate. A particularly preferred water-insoluble component iscellulose acetate. Particularly preferred cellulose acetates includethose having an acetyl content of about 40 percent and a hydroxylcontent of about 3.5 percent. Other materials also can be used in thefabrication of asymmetric membrane technology coatings, provided suchmaterials are substantially water-insoluble, film-forming and safe touse in pharmaceutical applications.

In the preparation of the asymmetric membrane coatings of the presentinvention, the water-soluble polymeric component of the presentinvention comprises solid, polymeric materials that do not form hydrogenperoxide or formaldehyde upon storage for 12 weeks at 40 degrees C./75percent relative humidity, in an amount greater than about 0.01 percentw/w (100 parts per million, ppm). In terms of water solubility, thesolid polymeric water-soluble material preferentially has awater-solubility of greater than 0.5 mg/mL; more preferably, greaterthan 2 mg/mL; and still more preferably, greater than 5 mg/mL.

The solid polymeric water-soluble material has a melting or softeningtemperature above room temperature. Preferentially, the solid materialhas a melting or softening temperature above 30 degrees C.; morepreferentially, above 40 degrees C.; and most preferentially, above 50degrees C. Melting and softening points can be determined visually usinga melting point apparatus, or alternatively, can be measured usingdifferential scanning calorimetry (DSC), as is known in the art. Thepolymer can be either a homopolymer or a copolymer. Such polymers can benatural polymers, or be derivatives of natural products, or be entirelysynthetic. The molecular weight of such materials is preferentially highenough to prevent migration and aid in film-forming, yet low enough toallow coating (as discussed below). The preferred molecular weight rangefor the present invention is therefore between 2000 and 50,000 daltons(weight average). Preferred polymers suitable as water-solublecomponents of an asymmetric membrane technology coating for the presentinvention include substituted, water-soluble cellulose derivatives,acacia, dextrin, guar gum, maltodextrin, sodium alginate, starch,polyacrylates, polyvinyl alcohols and zein. Particularly preferredwater-soluble polymers include hydroxyethylcellulose,hydroxypropylcellulose and polyvinylalcohol.

It is difficult to obtain asymmetric membrane coatings if the viscosityof the coating solution is too high, and that one approach to solvingthis issue is to use more dilute solutions of the polymer. Due to thephase behavior of the coating solution, having both water-soluble andorganic-soluble components, there is a limit to how low theconcentration of the water-soluble polymer can be and still provide acommercializable process. For this reason, it is preferred that thewater-soluble polymers not have too high a viscosity. Viscosities can bedetermined at 25 degrees C. using a Brookfield LVF viscometer (availablefrom Brookfield Engineering Corp., Middleboro, Mass.) with spindle andspeed combinations depending on viscosity levels for 5 percent (w:w)aqueous solutions. Preferred water-soluble polymers have viscosities for5 percent (w:w) solutions of less than 400 mPa s; more preferably, lessthan 300 mPa s.

Using the above criteria, especially preferred water-soluble polymersinclude hydroxypropylcellulose and hydroxyethylcellulose having aviscosity for a 5 percent (w:w) of less than 300 mPa s. Commerciallyavailable examples of such polymers include Klucel EF™ and Natrasol LR™,both made by the Aqualon Division of Hercules Corp., Hopewell, Va.

The water-soluble, solid polymeric material's stability to formation ofhydrogen peroxide can be measured by storing the polymer in an ovenhaving a temperature and relative humidity (RH) of 40 degrees C. and 75percent RH, respectively. The polymer should be stored exposed to theoven environment under “open” conditions. The polymer should be storedfor at least 12 weeks. Levels of hydrogen peroxide can be administeredas described in G. M. Eisenberg, “Colorimetric determination of hydrogenperoxide” in Ind. Eng. Chem. (Anal. Ed.), 1943, 15, 327-328. Under thesestorage conditions, acceptable polymeric materials for the presentinvention have hydrogen peroxide levels below 100 parts per million(ppm); more preferably, below 50 ppm; and most preferably, below 10 ppm.

Similarly, the water-soluble polymer's stability to formation offormaldehyde can be measured by storing the polymer in an oven at 40degrees C. and 75 percent RH. Polymer should be stored in a sealedcontainer to avoid loss of volatile formaldehyde. The polymer should bestored for at least 12 weeks. Levels of formaldehyde can be determinedas described in M. Ashraf-Khorassani, et al., “Purification ofpharmaceutical excipients with supercritical fluid extraction” in Pharm.Dev. Tech. 2005, 10, 1-10. Under these storage conditions, acceptablewater-soluble polymeric materials for the present invention haveformaldehyde levels below 100 ppm, more preferably, below 50 ppm, andmost preferably, below 10 ppm.

It will be appreciated by those skilled in the art that the asymmetricmembrane technology coating formulation can contain small amounts ofother materials without significantly changing its function or alteringthe nature of the present invention. Such additives include glidants(e.g., talc and silica) and plasticizers (e.g., triethylcitrate andtriacetin), which are typically added, when needed, at levels of lessthan about 5 percent (w:w) of the coating.

It will be appreciated by those skilled in the art that activepharmaceutical ingredients can also be in the form of pharmaceuticallyacceptable salts. The cores for the present invention can also employsolubilizing additives. Such additives include pH-buffering additives tomaintain the core at a pH wherein the active pharmaceutical ingredienthas a sufficiently high solubility to be pumped out of the dosage formin solution. The active pharmaceutical ingredient can be present in thecore at levels ranging from about 0.1 percent (w:w) to about 75 percent(w:w).

The core can contain osmotic agents which help to provide the drivingforce for drug delivery. Such osmotic agents include water-solublesugars and salts. A particularly preferred osmotic agent is mannitol orsodium chloride.

The core of the AMT system can contain other additives to provide forsuch benefits as stability, manufacturability and system performance.Stabilizing excipients include pH-modifying ingredients, antioxidants,chelating agents, and other such additives as is known in the art.Excipients that improve manufacturability include agents to help inflow, compression or extrusion. Flow can be helped by such additives astalc, stearates and silica. Flow is also improved by granulation of thedrug and excipients, as is known in the art. Such granulations oftenbenefit from the addition of binders such as hydroxypropylcellulose,starch and polyvinylpyrollidone (povidone). Compression can be improvedby the addition of diluents to the formulation. Examples of diluentsinclude lactose, mannitol, microcrystalline cellulose and the like, asis known in the art. For cores produced by extrusion, the meltproperties of the excipients can be important. Generally, it ispreferable that such excipients have melting temperatures below about100 degrees C. Examples of appropriate excipients for melt processesinclude esterified glycerines and stearyl alcohol. For compressed dosageforms, manufacturability can be improved by addition of lubricants. Aparticularly preferred lubricant is magnesium stearate.

Cores can be produced using standard tablet compression processes, as isknown in the art. Such processes involve powders filling dies followedby compression using appropriate punches. Cores can also be produced byan extrusion process. Extrusion processes are especially well-suited tomaking small cores (multiparticulates). A preferred extrusion process isa melt-spray-congeal process as described in WO2005/053653A1,incorporated by reference. Cores can also be prepared by layering drugonto seed cores. Such seed cores are preferentially made of sugar ormicrocrystalline cellulose. Drug can be applied onto the cores byspraying, preferentially in a fluid-bed operation, as is known in theart.

In the practice of the subject invention, the cores are coated with theasymmetric membrane by any technique that can provide the asymmetricmembrane as a coating over the entire cores. Preferred coating methodsinclude pan coating and fluid-bed coating. In both coating processes,the water-insoluble polymer and water-soluble polymer as well as anyother additives are first dissolved or dispersed in an appropriatesolvent or solvent combination. In order to achieve a suitably porousmembrane, the coating solvent needs to be optimized for performance.Generally, the solvents are chosen such that the more volatile solventis the better solvent for the water-insoluble polymeric component. Theresult is that during coating, the water-insoluble polymeric componentprecipitates from solution. Preferred solvents and solvent ratios can bedetermined by examining the multi-component solubility behavior of thesystem. A preferred solvent mixture is acetone and water, with a ratioof between about 9:1 and about 6:4, w:w.

In a preferred embodiment of the present invention, tofacitinib isincorporated into a monolithic osmotic delivery device, known as anextrudable core system, such that the tofacitinib-containing compositionmust include viscosifying polymers and osmoticallly active agents, andmay optionally include solubility enhancing agents and/or antioxidants.The monolithic tablet or capsule is surrounded by a semi-permeablemembrane which contains one or more openings which are manufactured intothe dosage form through such techniques as laser drilling. Theviscosifying polymers suspend or entrain the drug so as to aid in thedelivery of the drug through the delivery port(s). While not wishing tobe bound by any particular theory, it is believed that upon theimbibition of water into the dosage form, the viscosifying polymer hasenough viscosity to allow it to suspend or entrain the drug, while atthe same time remaining sufficiently fluid to allow the viscosifyingpolymer to pass through the delivery port(s) along with the drug. Theamount of the viscosifying polymer present in the tofacitinib-containingcomposition may range from about 2 wt % to about 20 wt %, preferablyfrom about 3 to about 15%, and more preferably from about 4 wt % toabout 10 wt %. The viscosifying polymer may be a single material or amixture of materials. Non-crosslinked polyethylene oxide (PEO) andHydroxyethyl cellulose (HEC) may be used as the viscosifying polymers.HEC is preferred as the viscosifying polymer. The molecular weight ofHEC can be from about 300,000 to about 2,000,000, more preferablybetween about 700,000 to about 1,500,000).

The tofacitinib-containing composition also includes osmoticallyeffective solutes, often referred to as “osmogens” or “osmagents.” Theamount of osmagent present in the tofacitinib-containing composition mayrange from about 15 wt % to about 95 wt %, preferably from about 40 wt %to about 90 wt %, more preferably about 60% to about 85%, and mostpreferably about 70% to about 85%, of the tofacitinib-containingcomposition. Typical classes of suitable osmagents are water-solublesalts, sugars, organic acids, and other low-molecule-weight organiccompounds that are capable of imbibing water to thereby establish anosmotic pressure gradient across the barrier of the surrounding coating.Typical useful salts include magnesium sulfate, magnesium chloride,calcium chloride, sodium chloride, lithium chloride, potassium sulfate,sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride,and sodium sulfate. Preferred salts include as sodium chloride andpotassium chloride. Preferred organic acids include ascorbic acid,2-benzene carboxylic acid, benzoic acid, fumaric acid, citric acid,maleic acid, serbacic acid, sorbic acid, edipic acid, editic acid,glutamic acid, toluene sulfonic acid, and tartaric acid. Preferredsugars include mannitol, sucrose, sorbitol, xylitol, lactose, dextrose,and trehalose. A more preferred sugar is sorbitol. The osmagents can beused alone or as a combination of two or more osmagents.

The tofacitinib-containing composition may further includesolubility-enhancing agents or solubilizers that promote the aqueoussolubility of the drug, present in an amount ranging from about 0 toabout 30 wt % of the tofacitinib-containing composition. Solubilizersuseful with tofacitinib include organic acids and organic acid salts,partial glycerides, e.g., less than fully esterified derivatives ofglycerin, including glycerides, monoglycerides, diglycerides, glyceridederivatives, polyethylene glycol esters, polypropylene glycol esters,polyhydric alcohol esters, polyoxyethylene ethers, sorbitan esters,polyoxyethylene sorbitan esters, and carbonate salts.

A preferred class of solubilizers is organic acids. Since tofacitinib isa base which is solubilized by protonation, and since its solubility inan aqueous environment of pH 5 or higher is reduced, it is believed thataddition of an organic acid to the Tofacitinib-containing compositionassists in solubilization and hence absorption of tofacitinib. Even aslight decrease in the pH of the aqueous solution at high pH results indramatic increases in the solubility of tofacitinib. Organic acids canalso promote stability during storage prior to introduction to a useenvironment due to their tendency to maintain tofacitinib in aprotonated state.

There are a variety of factors to consider when choosing an appropriateorganic acid for use as a solubilizer with tofacitinib in an osmoticdosage form. The acid should not interact adversely with tofacitinib,should have appropriate water solubility, and should provide goodmanufacturing properties.

Accordingly, it has been found that a preferred subset of organic acidsmeeting such criteria consists of citric, succinic, fumaric, adipic,malic and tartaric acids. Citric, malic, and tartaric acid have theadvantage of high water solubility and high osmotic pressure. Succinicand fumaric acid offer a combination of both moderate solubility andmoderate osmotic pressure.

The tofacitinib-containing composition layer and/or the functional ratecontrolling membrane may optionally contain an antioxidant, such as butnot limited to BHT, BHA, sodium metabisulfite, propyl galate, glycerin,vitamin E, Citric Acid or ascorbyl palmitate. The antioxidant may bepresent in an amount ranging from 0 to 10 wt % of thetofacitinib-containing composition layer and/or the water-swellablecomposition layer and/or the functional rate controlling membrane. Foradditional examples of antioxidants, see C.-M. Andersson, A. Hallberg,and T. Hoegberg. Advances in the development of pharmaceuticalantioxidants. Advances in Drug Research. 28:65-180, 1996.

The Tofacitinib-containing composition is prepared by mixing theviscosifying polymer and the other excipients to form a uniform blend.To obtain a uniform blend, it is desirable to either wet or drygranulate or dry blend the components using the types of processes knownto those skilled in the art.

Tableting

The core is prepared by first placing a mixture of thetofacitinib-containing composition into a tablet press and compressed inorder to complete formation of the core. Tablet shapes may include anytablet shape known to those skilled in the art. Preferable tablet shapesinclude SRC (standard round concave), oval, modified oval, capsule,caplet, and almond. More preferable tablet shapes include oval, modifiedoval, caplet, and capsule.

The Coating

Following formation of the core, the semi-permeable coating is applied.The coating should have high water permeability and a high strength,while at the same time be easily fabricated and applied. High waterpermeability is required to permit water to enter the core in sufficientvolume. High strength is required to ensure the coating does not burstwhen the core swells as it imbibes water, leading to an uncontrolleddelivery of the core contents. Finally, the coating must have highreproducibility and yield.

It is essential that the coating have at least one delivery port incommunication with the interior and exterior of the coating for deliveryof the tofacitinib-containing composition. Furthermore, the coating mustbe non-dissolving and non-eroding during release of thetofacitinib-containing composition, generally meaning that it bewater-insoluble, such that tofacitinib is substantially entirelydelivered through the delivery port(s), in contrast to delivery viapermeation through the coating.

Coatings with these characteristics can be obtained using hydrophilicpolymers such as plasticized and unplasticized cellulose esters, ethers,and ester-ethers. Particularly suitable polymers include celluloseacetate (CA), cellulose acetate butyrate (CAB), and ethyl cellulose(EC). One set of polymers are cellulose acetates having acetyl contentsof 25 to 42%. One typical polymer is CA having an acetyl content of39.8%, specifically, CA 398-10 (Eastman Fine Chemicals, Kingsport,Tenn.). CA 398-10 is reported to have an average molecular weight ofabout 40,000 daltons. Another typical CA having an acetyl content of39.8% is high molecular weight CA having an average molecular weightgreater than about 45,000, and specifically, CA 398-30 (Eastman FineChemical) which is reported to have an average molecular weight of50,000 daltons.

Coating is conducted in conventional fashion by first forming a coatingsolution and then coating by dipping, fluidized bed coating, or by pancoating. To accomplish this, a coating solution is formed comprising thepolymer and a solvent. Typical solvents useful with the cellulosicpolymers above include acetone, methyl acetate, ethyl acetate, isopropylacetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone,ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate,methylene dichloride, ethylene dichloride, propylene dichloride,nitroethane, nitropropane, tetrachloroethane, 1,4-dioxane,tetrahydrofuran, diglyme, and mixtures thereof. The coating solutiontypically contains 2 to 15 wt % of the polymer.

The coating solution may also include pore-formers or non-solvents inany amount as long as the polymer remains soluble at the conditions usedto form the coating and as long as the coating remains water permeableand has sufficient strength. Pore-formers and their use in fabricatingcoatings are described in U.S. Pat. Nos. 5,698,220 and 5,612,059, thepertinent disclosures of which are incorporated herein by reference. Theterm “pore former,” as used herein, refers to a material added to thecoating solution that has low or no volatility relative to the solventsuch that it remains as part of the coating following the coatingprocess but that is sufficiently water swellable or water soluble suchthat, in the aqueous use environment it provides a water-filled orwater-swollen channel or “pore” to allow the passage of water, therebyenhancing the water permeability of the coating. Suitable pore formersinclude but are not limited to hydroxypropylcellulose (HPC),polyethylene glycol (“PEG”), PVP, and PEO. To obtain a combination ofhigh water permeability and high strength when PEG or HPC are used as apore former, the weight ratio of CA:PEG or CA:HPC should range fromabout 6:4 to about 9:1. CA:HPC is a preferred coating composition.Preferred CA:HPC weight ratios should range from 6:4 to 7:3. PreferredCA:PEG weight ratios should range from 6:4 to 7:3.

The addition of a non-solvent such as water or methanol to the coatingsolution results in exceptional performance. By “non-solvent” is meantany material added to the coating solution that substantially dissolvesin the coating solution and reduces the solubility of the coatingpolymer or polymers in the solvent. In general, the function of thenon-solvent is to impart porosity to the resulting coating. As describedbelow, porous coatings have higher water permeability than an equivalentweight of a coating of the same composition that is not porous and thisporosity is indicated by a reduction in the density of the coating(mass/volume). Although not wishing to be bound by any particularmechanism of pore formation, it is generally believed that addition of anon-solvent imparts porosity to the coating during evaporation ofsolvent by causing the coating solution to undergo liquid and liquidphase separation prior to solidification. The suitability and amount ofa particular candidate material can be evaluated for use as anon-solvent by progressively adding the candidate non-solvent to thecoating solution until it becomes cloudy. If this does not occur at anyaddition level up to about 50 wt % of the coating solution, it generallyis not appropriate for use as a non-solvent. When clouding is observed,termed the “cloud point,” an appropriate level of non-solvent formaximum porosity is the amount just below the cloud point. For acetonesolutions comprising 7 wt CA and 3 wt % PEG, the cloud point is at about23 wt % water. When lower porosities are desired, the amount ofnon-solvent can be reduced as low as desired.

Suitable non-solvents are any materials that have appreciable solubilityin the solvent and that lower the coating polymer solubility in thesolvent. The preferred non-solvent depends on the solvent and thecoating polymer chosen. In the case of using a volatile polar coatingsolvent such as acetone, suitable non-solvents include water, glycerol,alcohols such as methanol or ethanol.

When using CA 398-10, coating solution weight ratios of CA:PEG 3350:water are 2.4:1.6:5, 2.8:1.2:5, 3.2:0.8:5, and 3.6:0.4:5, with theremainder of the solution comprising a solvent such as acetone. Thus,for example, in a solution having a weight ratio of CA:PEG 3350: waterof 2.8:1.2:5, CA comprises 2.8 wt % of the solution, PEG 3350 comprises1.2 wt % of the solution, water comprises 5 wt % of the solution, andacetone comprises the remaining 91 wt %. Likewise, coating solutionweight ratios of CA:HPC:water are 1.2:0.8:9.8, 2.4:1.6:19.6,1.6:0.4:4.9, and 3.2:0.8:9.8, with the remainder of the solutioncomprising a solvent such as acetone. Thus, for example, in a solutionhaving a weight ratio of CA:HPC:water of 1.2:0.8:10, CA comprises 1.2 wt% of the solution, HPC comprises 0.8 wt % of the solution, watercomprises 10 wt % of the solution, and acetone comprises the remaining88 wt %. Further, coating solution weight ratios of CA:HPC:methanol are1.8:1.2:19.6, 2.4:1.6:19.6, 1.6:0.4:4.9, and 3.2:0.8:9.8, with theremainder of the solution comprising a solvent such as acetone. Thus,for example, in a solution having a weight ratio of CA:HPC:methanol of1.8:1.2:19.6, CA comprises 1.8 wt % of the solution, HPC comprises 1.2wt % of the solution, methanol comprises 19.6 wt % of the solution, andacetone comprises the remaining 77.4 wt %.

When incorporating antioxidants into the coating solution, a thirdsolvent may be required to ensure good dispersion of the antioxidantinto the coating. For example, a CA:PEG:water composition of 2.4:1.6:5that includes 0.05 wt % of antioxidant of the solution requires 5 wt %methanol and 86% acetone.

Coatings formed from these coating solutions are generally porous. By“porous” is meant that the coating in the dry state has a density lessthan the density of the same material in a nonporous form. By “nonporousform” is meant a coating material formed by using a coating solutioncontaining no non-solvent, or the minimal amount of non-solvent requiredto produce a homogeneous coating solution. The dry-state density of thecoating can be calculated by dividing the coating weight (determinedfrom the weight gain of the tablets before and after coating) by thecoating volume (calculated by multiplying the coating thickness, asdetermined by optical or scanning electron microscopy, by the tabletsurface area). The porosity of the coating is one of the factors thatleads to the combination of high water permeability and high strength ofthe coating.

The weight of the coating around the core depends on the composition andporosity of the coating, but generally should be present in an amountranging from 3 to 30 wt %, based on the weight of the uncoated core. Acoating weight of at least about 5 wt %, is typically preferred forsufficient strength for reliable performance, although lower coatingweights can be used to achieve desire high water imbibing rates and,subsequently, higher release rates of tofacitinib from the dosage form.For tofacitinib-containing dosage forms, a coating weight gain of 5-10%is preferred to achieve the desired release performance.

While porous coatings based on CA, PEG or HPC, and water or methanoldescribed above translate to excellent results, other pharmaceuticallyacceptable materials could be used in the coating so long as the coatinghas the requisite combination of high water permeability, high strength,and ease of fabrication and application. Further, such coatings may bedense, porous, or “asymmetric,” having one or more dense layers and oneor more porous layers such as those disclosed in U.S. Pat. Nos.5,612,059 and 5,698,220, the pertinent disclosures of which areincorporated herein by reference.

The coating must also contain at least one delivery port incommunication with the interior and exterior of the coating to allow forrelease of the tablet core contents to the exterior of the dosage form.The delivery port can range in size from about the size of the drugparticles, and thus could be as small as 1 to 100 microns in diameterand may be termed pores, up to about 5000 microns in diameter. The shapeof the port may be substantially circular, in the form of a slit, orother convenient shape to ease manufacturing and processing. The port(s)may be formed by post-coating mechanical or thermal means or with a beamof light (e.g., a laser), a beam of particles, or other high-energysource, or may be formed in situ by rupture of a small portion of thecoating. Such rupture may be controlled by intentionally incorporating arelatively small weak portion into the coating. Delivery ports may alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the coating over an indentation in thecore. Delivery ports may be formed by coating the core such that one ormore small regions remain uncoated. In addition, the delivery port canbe a large number of holes or pores that may be formed during coating,as in the case of asymmetric membrane coatings, described in more detailherein, and of the type disclosed in U.S. Pat. Nos. 5,612,059 and5,698,220, the disclosures of which are incorporated by reference. Whenthe delivery pathways are pores there can be a multitude of such poresthat range in size from 1 micron to greater than 100 microns. Duringoperation, one or more of such pores may enlarge under the influence ofthe hydrostatic pressure generated during operation. The location of thedelivery port(s) may be located anywhere on the tablet surface.Preferred locations of the delivery port(s) include the face of thetablet and the tablet band. A more preferred location includesapproximately the center of the tablet band for round, SRC-shapedtablets and approximately the center of the tablet band along the majoraxis and/or approximately the center of the tablet band along the minoraxis of the tablet band for capsule, caplet, oval, or modified ovalshaped tablets. A most preferred location of the delivery port(s) is theapproximate center of the tablet band along the major axis of the tabletband for capsule, caplet, oval, or modified oval shaped tablets.

Sustained Release—Reservoir Systems

Another class of tofacitinib sustained-release dosage forms of thisinvention includes membrane-moderated or reservoir systems. In thisclass, a reservoir of tofacitinib is surrounded by a rate-limitingmembrane. The tofacitinib traverses the membrane by mass transportmechanisms well known in the art, including but not limited todissolution in the membrane followed by diffusion across the membrane ordiffusion through liquid-filled pores within the membrane. Theseindividual reservoir system dosage forms may be large, as in the case ofa tablet containing a single large reservoir, or multiparticulate, as inthe case of a capsule containing a plurality of reservoir particles,each individually coated with a membrane. The coating can be non-porous,yet permeable to tofacitinib (for example tofacitinib may diffusedirectly through the membrane), or it may be porous. As with otherembodiments of this invention, the particular mechanism of transport isnot believed to be critical.

Sustained release coatings as known in the art may be employed tofabricate the membrane, especially polymer coatings, such as a celluloseester or ether, an acrylic polymer, or a mixture of polymers. Preferredmaterials include ethyl cellulose, cellulose acetate and celluloseacetate butyrate. The polymer may be applied as a solution in an organicsolvent or as an aqueous dispersion or latex. The coating operation maybe conducted in standard equipment such as a fluid bed coater, a Wurstercoater, or a rotary bed coater.

If desired, the permeability of the coating may be adjusted by blendingof two or more materials. A useful process for tailoring the porosity ofthe coating comprises adding a pre-determined amount of a finely-dividedwater-soluble material, such as sugars or salts or water-solublepolymers to a solution or dispersion (e.g., an aqueous latex) of themembrane-forming polymer to be used. When the dosage form is ingestedinto the aqueous medium of the GI tract, these water soluble membraneadditives are leached out of the membrane, leaving pores whichfacilitate release of the drug. The membrane coating can also bemodified by the addition of plasticizers, as known in the art.

A useful variation of the process for applying a membrane coatingcomprises dissolving the coating polymer in a mixture of solvents chosensuch that as the coating dries, a phase inversion takes place in theapplied coating solution, resulting in a membrane with a porousstructure. Numerous examples of this type of coating system are given inEuropean Patent Specification 0 357 369 B1, published Mar. 7, 1990,herein incorporated by reference.

The morphology of the membrane is not of critical importance so long asthe permeability characteristics enumerated herein are met. The membranecan be amorphous or crystalline. It can have any category of morphologyproduced by any particular process and can be, for example, aninterfacially-polymerized membrane (which comprises a thin rate-limitingskin on a porous support), a porous hydrophilic membrane, a poroushydrophobic membrane, a hydrogel membrane, an ionic membrane, and othersuch materials which are characterized by controlled permeability totofacitinib.

A useful reservoir system embodiment is a capsule having a shellcomprising the material of the rate-limiting membrane, including any ofthe membrane materials previously discussed, and filled with atofacitinib drug composition. A particular advantage of thisconfiguration is that the capsule may be prepared independently of thedrug composition, thus process conditions that would adversely affectthe drug can be used to prepare the capsule. One embodiment is a capsulehaving a shell made of a porous or a permeable polymer made by a thermalforming process. Another embodiment is a capsule shell in the form of anasymmetric membrane; e.g., a membrane that has a thin skin on onesurface and most of whose thickness is constituted of a highly permeableporous material. A process for preparation of asymmetric membranecapsules comprises a solvent exchange phase inversion, wherein asolution of polymer, coated on a capsule-shaped mold, is induced tophase-separate by exchanging the solvent with a-miscible non-solvent.Examples of asymmetric membranes useful in this invention are disclosedin the aforementioned European Patent Specification 0 357 369 B1.

Another embodiment of the class of reservoir systems comprises amultiparticulate wherein each particle is coated with a polymer designedto yield sustained release of tofacitinib. The multiparticulateparticles each comprise tofacitinib and one or more excipients as neededfor fabrication and performance. The size of individual particles, aspreviously mentioned, is generally between about 50 micron and about 3mm, although beads of a size outside this range may also be useful. Ingeneral, the beads comprise tofacitinib and one or more binders. As itis generally desirable to produce dosage forms which are small and easyto swallow, beads which contain a high fraction of tofacitinib relativeto excipients are preferred. Binders useful in fabrication of thesebeads include microcrystalline cellulose (e.g., Avicel®, FMC Corp.),hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC),and related materials or combinations thereof. In general, binders whichare useful in granulation and tabletting, such as starch, pregelatinizedstarch, and poly(N-vinyl-2-pyrrolidinone) (PVP) may also be used to formmultiparticulates.

Reservoir system tofacitinib multiparticulates may be prepared usingtechniques known to those skilled in the art, including, but not limitedto, the techniques of extrusion and spheronization, wet granulation,fluid bed granulation, and rotary bed granulation. In addition, thebeads may also be prepared by building the tofacitinib composition (drugplus excipients) up on a seed core (such as a non-pareil seed) by adrug-layering technique such as powder coating or by applying thetofacitinib composition by spraying a solution or dispersion oftofacitinib in an appropriate binder solution onto seed cores in afluidized bed such as a Wurster coater or a rotary processor. An exampleof a suitable composition and method is to spray a dispersion of atofacitinib/hydroxypropylcellulose composition in water. Advantageously,tofacitinib can be loaded in the aqueous composition beyond itssolubility limit in water.

A method for manufacturing the multiparticulate cores of this embodimentis the extrusion/spheronization process, as previously discussed formatrix multiparticulates. Another process and composition for thismethod involves using water to wet-mass blend of about 5 to 75% ofmicro-crystalline cellulose with correspondingly about 95 to 25%tofacitinib. In another embodiment, the process involves the use ofwater to wet-mass blend of about 5-30% microcrystalline cellulose withcorrespondingly about 5-70% tofacitinib.

A sustained release coating as known in the art, especially polymercoatings, may be employed to fabricate the membrane, as previouslydiscussed for reservoir systems. Suitable and preferred polymer coatingmaterials, equipment, and coating methods also include those previouslydiscussed.

The rate of tofacitinib release from the coated multiparticulates canalso be controlled by factors such as the composition and binder contentof the drug-containing core, the thickness and permeability of thecoating, and the surface-to-volume ratio of the multiparticulates. Itwill be appreciated by those skilled in the art that increasing thethickness of the coating will decrease the release rate, whereasincreasing the permeability of the coating or the surface-to-volumeratio of the multiparticulates will increase the release rate. Ifdesired, the permeability of the coating may be adjusted by blending oftwo or more materials. A useful series of coatings comprises mixtures ofwater-insoluble and water-soluble polymers, for example, ethylcelluloseand hydroxypropyl methylcellulose, respectively. A useful modificationto the coating is the addition of finely-divided water-soluble material,such as sugars or salts. When placed in an aqueous medium, these watersoluble membrane additives are leached out of the membrane, leavingpores which facilitate delivery of the drug. The membrane coating mayalso be modified by the addition of plasticizers, as is known to thoseskilled in the art. Another useful variation of the membrane coatingutilizes a mixture of solvents chosen such that as the coating dries, aphase inversion takes place in the applied coating solution, resultingin a membrane with a porous structure.

Another embodiment is a multiparticulate comprising about 5-50%tofacitinib, the individual particles being coated with an aqueousdispersion of ethyl cellulose, which dries to form a continuous film.

Another embodiment is obtained when the tofacitinib beads are less thanabout 400 micron in size and are coated with a phase inversion membraneof ethyl cellulose or cellulose acetate.

Another embodiment is obtained when the tofacitinib beads are less thanabout 400 micron in size and are coated with an aqueous dispersion ofethyl cellulose, which dries to form a continuous film.

Another embodiment is obtained when the tofacitinib beads are less thanabout 300 micron in size and are coated with an aqueous dispersion ofethyl cellulose, which dries to form a continuous film.

Delayed Release and Controlled Release Components

Another class of dosage forms includes those forms which incorporate adelay before the onset of controlled release of tofacitinib. Oneembodiment can be illustrated by a tablet comprising a core containingtofacitinib coated with a first coating of a polymeric material of thetype useful for controlled release of tofacitinib and a second coatingof the type useful for delaying release of drugs when the dosage form isingested. The first coating is applied over and surrounds the tablet.The second coating is applied over and surrounds the first coating.

The tablet can be prepared by techniques well known in the art andcontains a therapeutically useful amount of tofacitinib plus suchexcipients as are necessary to form the tablet by such techniques.

The first coating may be a controlled release coating as known in theart, especially polymer coatings, to fabricate the membrane, aspreviously discussed for reservoir systems. Suitable polymer coatingmaterials, equipment, and coating methods also include those previouslydiscussed.

Materials useful for preparing the second coating on the tablet includepolymers known in the art as enteric coatings for delayed-release ofpharmaceuticals. These most commonly are pH-sensitive materials such ascellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methyl cellulose phthalate, poly(vinyl acetate phthalate),and acrylic copolymers such as Eudragit L-100 (RohmPharma), Eudragit L30 D-55, Eudragit S 100, Eudragit FS 30D, and related materials, as morefully detailed below under “Delayed Release”. The thickness and type ofthe delayed-release coating is adjusted to give the desired delayproperty. In general, thicker coatings are more resistant to erosionand, consequently, yield a longer delay as do coatings which aredesigned to dissolve above pH 7. Preferred coatings typically range fromabout 10 micron in thickness to about 3 mm in thickness and morepreferably 10 um to 500 um.

When ingested, the twice-coated tablet passes through the stomach, wherethe second coating prevents release of the tofacitinib under the acidicconditions prevalent there. When the tablet passes out of the stomachand into the small intestine, where the pH is higher, the second coatingerodes or dissolves according to the physicochemical properties of thechosen material. Upon erosion or dissolution of the second coating, thefirst coating prevents immediate or rapid release of the tofacitinib andmodulates the release so as to prevent the production of highconcentrations, thereby minimizing side-effects.

Another embodiment comprises a multiparticulate wherein each particle isdual coated as described above for tablets, first with a polymerdesigned to yield controlled release of the tofacitinib and then coatedwith a polymer designed to delay onset of release in the environment ofthe GI tract when the dosage form is ingested. The beads containtofacitinib and may contain one or more excipients as needed forfabrication and performance. Multiparticulates which contain a highfraction of tofacitinib relative to binder are desired. Themultiparticulate may be of a composition and be fabricated by any of thetechniques previously disclosed for multiparticulates used to makereservoir systems (including extrusion and spheronization, wetgranulation, fluid bed granulation, and rotary bed granulation, seedbuilding, and so forth).

The controlled release coating may be as known in the art, especiallypolymer coatings, to fabricate the membrane, as previously discussed forreservoir systems. Suitable polymer coating materials, equipment, andcoating methods also include those previously discussed.

The rate of tofacitinib release from the controlled-release-coatedmultiparticulates (e.g., the multiparticulates before they receive thedelayed-release coating) and methods of modifying the coating are alsocontrolled by the factors previously discussed for reservoir systemtofacitinib multiparticulates.

The second membrane or coating for dual coated multiparticulates is adelayed-release coating which is applied over the firstcontrolled-release coating, as disclosed above for tablets, and may beformed from the same materials. It should be noted that the use of theso-called “enteric” materials to practice this embodiment differssignificantly from their use to produce conventional enteric dosageforms. With conventional enteric forms, the object is to delay releaseof the drug until the dosage form has passed the stomach and then todeliver the dose shortly after emptying from the stomach. Dosing oftofacitinib directly and completely to the duodenum is undesirable,however, due to local metabolism which is sought to be minimized oravoided by this invention. Therefore, if conventional enteric polymersare to be used to practice this embodiment, it may be necessary to applythem significantly more thickly than in conventional practice, in orderto delay drug release until the dosage form reaches the lower GI tract.However, it is preferred to effect a controlled delivery of tofacitinibafter the delayed-release coating has dissolved or eroded, therefore thebenefits of this embodiment may be realized with a proper combination ofdelayed-release character with controlled-release character, and thedelayed-release part alone may or may not necessarily conform to USPenteric criteria. The thickness of the delayed-release coating isadjusted to give the desired delay property. In general, thickercoatings are more resistant to erosion and, consequently, yield a longerdelay.

It should also be noted, that sustained release osmotic systems asdefined above, could also be defined in the current delay thencontrolled release category. Typical osmotic sustained release systemshave an initial delay of 0.5-6 hours prior to drug release in acontrolled fashion. In this manner, a standard osmotic monolithic orbilayer sustained release system embodies the definition of delayfollowed by controlled release.

Bursting Osmotic Beads and Cores (Pulsatile Delivery)

In a further embodiment (“bursting osmotic core device”), tofacitinib isincorporated in an osmotic bursting device which comprises a tablet coreor bead core containing tofacitinib and, optionally, one or moreosmagents. Devices of this type have been generally disclosed in Baker,U.S. Pat. No. 3,952,741, which is incorporated herein by reference.Examples of osmagents are sugars such as glucose, sucrose, mannitol,lactose, and the like; and salts such as sodium chloride, potassiumchloride, sodium carbonate, and the like; water-soluble acids such astartaric acid, fumaric acid, and the like. The tofacitinib-containingtablet core or bead core is coated with a polymer which forms asemipermeable membrane, that is, a membrane which is permeable to waterbut is substantially impermeable to tofacitinib. Examples of polymerswhich provide a semipermeable membrane are cellulose acetate, celluloseacetate butyrate, and ethylcellulose, preferably cellulose acetate. Thesemipermeable coating membrane may alternatively be composed of one ormore waxes, such as insect and animal waxes such as beeswax, andvegetable waxes such as carnauba wax and hydrogenated vegetable oils. Amelt mixture of a polyethylene glycol, e.g., polyethylene glycol-6000,and a hydrogenated oil, e.g., hydrogenated castor oil, may be used as acoating, as described for isoniazid tablets by Yoshino (CapsugelSymposia Series; Current Status on Targeted Drug Delivery to theGastrointestinal Tract; 1993; pp. 185-190). Some preferred semipermeablecoating materials are cellulose esters and cellulose ethers, polyacrylicacid derivatives such as polyacrylates and polyacrylate esters, andpolyvinyl alcohols and polyalkenes such as ethylene vinyl alcoholcopolymer. Other semipermeable coating materials are cellulose acetateand cellulose acetate butyrate.

When a coated tablet or bead of the “bursting osmotic core” embodimentof this invention is placed in an aqueous environment of use, waterpasses through the semipermeable membrane into the core, dissolving aportion of the tofacitinib and osmagent, generating a colloidal osmoticpressure which results in bursting of the semipermeable membrane andrelease of tofacitinib into the aqueous environment. By choice of beador tablet core size and geometry, identity and quantity of osmagent, andthickness of the semipermeable membrane, the time lag between placementof the dosage form into the aqueous environment of use and release ofthe enclosed tofacitinib may be chosen. It will be appreciated by thoseskilled in the art that increasing the surface-to-volume ratio of thedosage form, and increasing the osmotic activity of the osmagent serveto decrease the time lag, whereas increasing the thickness of thecoating will increase the time lag. Osmotic-bursting devices of thisinvention are those which exhibit substantially no release oftofacitinib from the dosage form until the dosage form has exited thestomach and has resided in the small intestine for about 15 minutes orgreater. Some osmotic-bursting devices exhibit substantially no releaseof tofacitinib from the dosage form until the dosage form has exited thestomach and has resided in the small intestine for about 30 minutes orgreater. Other osmotic-bursting devices exhibit substantially no releaseof tofacitinib from the dosage form until the dosage form has exited thestomach and has resided in the small intestine for about 90 minutes orgreater. Still other osmotic-bursting devices exhibit substantially norelease of tofacitinib from the dosage form until the dosage form hasexited the stomach and has resided in the small intestine for and mostpreferably 3 hours or greater, thus assuring that minimal tofacitinib isreleased in the duodenum and upper small intestine. A bursting osmoticcore tablet or bead has a tablet or bead core which may contain fromabout 10-95% tofacitinib, about 0-60% osmagent, as described above, andabout 5-20% other pharmaceutical aids such as binders and lubricants.The semipermeable membrane coating on a tablet, such as a celluloseacetate coating, is present at a weight corresponding to from about 2%to about 30%, preferably from about 3% to about 10%, of the weight ofthe tablet core. The semipermeable membrane coating on a bead, such as acellulose acetate coating, is present at a weight corresponding to fromabout 2% to about 80% of the weight of the bead core. In anotherembodiment, the semipermeable coating on a bead is present at a weightcorresponding to from 3% to 30% of the weight of the bead core.

A bursting osmotic core device possesses no mechanism for “sensing” thatthe device has exited the stomach and entered the duodenum. Thus devicesof this type release tofacitinib at a predetermined time after enteringan aqueous environment, e.g., after being swallowed. In the fastedstate, indigestible non-disintegrating solids, such as the “burstingosmotic core devices” of this invention, are emptied from the stomachduring phase III of the Interdigestive Migrating Myoelectric Complex(IMMC), which occurs approximately every 2 hr in the human. Depending onthe stage of the IMMC at the time of dosing in the fasted state, abursting osmotic core device may exit the stomach almost immediatelyafter dosing, or as long as 2 hr after dosing. In the fed state,indigestible non-disintegrating solids, which are <11 mm in diameter,will empty slowly from the stomach with the contents of the meal (Khoslaand Davis, Int. J. Pharmaceut. 62 (1990) R9-R11). If the indigestiblenon-disintegrating solid is greater than about 11 mm in diameter, e.g.,about the size of a typical tablet, it will be retained in the stomachfor the duration of the digestion of the meal, and will exit into theduodenum during phase III of an IMMC, after the entire meal has beendigested and has exited the stomach. The release of tofacitinib can bedelayed until about 15 min or more. The release of tofacitinib can bedelayed until 30 minutes or more. The release of tofacitinib can bedelayed until about 90 minutes or greater. The release of tofacitinibcan be delayed until about 3 hours or greater after the dosage form hasexited the stomach. A bursting osmotic core device starts to releasetofacitinib at about 2.5 hr after entering an aqueous environment, e.g.,after ingestion, to more reliably assure that the device releases itstofacitinib distal to the duodenum, when dosed in the fasted state.Another “bursting osmotic core device” will start to release tofacitinibat about 4 hr after entering an aqueous environment. This 4 hr delaypermits dosing in the fed state, and allows for an about 3.5 hrretention in the fed stomach, followed by an approximately 30 minutedelay after the dosage form has exited from the stomach. In this way,the release of tofacitinib into the most sensitive portion of thegastrointestinal tract, the duodenum, is minimized.

In a further embodiment, a “bursting coated swelling core”, atofacitinib-containing tablet or bead is prepared which also comprises25-70% of a swellable material, such as a swellable colloid (e.g.,gelatin), as described in Milosovich, U.S. Pat. No. 3,247,066,incorporated herein by reference. Swelling core materials are hydrogels,e.g., hydrophilic polymers which take up water and swell, such aspolyethylene oxides, polyacrylic acid derivatives such as polymethylmethacrylate, polyacrylamides, polyvinyl alcohol,poly-N-vinyl-2-pyrrolidone, carboxymethylcellulose, starches, and thelike. Swelling hydrogels for this embodiment include polyethyleneoxides, carboxymethylcellulose and croscarmellose sodium. Thecolloid/hydrogel-containing tofacitinib-containing core tablet or beadis coated, at least in part, by a semipermeable membrane. Examples ofpolymers which provide a semipermeable membrane are cellulose acetateand cellulose acetate butyrate, and ethylcellulose. The semipermeablecoating membrane may alternatively be composed of one or more waxes,such as insect and animal waxes such as beeswax, and vegetable waxessuch as carnauba wax and hydrogenated vegetable oils. A melt mixture ofa polyethylene glycol, e.g., polyethylene glycol-6000, and ahydrogenated oil, e.g., hydrogenated castor oil, may be used as acoating, as described for isoniazid tablets by Yoshino (CapsugelSymposia Series; Current Status on Targeted Drug Delivery to theGastrointestinal Tract; 1993; pp. 185-190). Some semipermeable coatingmaterials are cellulose esters and cellulose ethers, polyacrylic acidderivatives such as polyacrylates and polyacrylate esters, polyvinylalcohols and polyalkenes such as ethylene vinyl alcohol copolymer,cellulose acetate and cellulose acetate butyrate.

When a coated tablet or bead having a bursting coated swelling core isplaced in an aqueous environment of use, water passes through thesemipermeable membrane into the core, swelling the core and resulting inbursting of the semipermeable membrane and release of tofacitinib intothe aqueous environment. By choice of bead or tablet core size andgeometry, identity and quantity of swelling agent, and thickness of thesemipermeable membrane, the time lag between placement of the dosageform into the aqueous environment of use and release of the enclosedtofacitinib may be chosen. Preferred bursting coated swelling coredevices of this invention are those which exhibit substantially norelease of tofacitinib from the dosage form until the dosage form hasexited the stomach and has resided in the small intestine for about 15minutes or greater, preferably about 30 minutes or greater, thusassuring that minimal tofacitinib is released in the duodenum.

A bursting coated swelling core tablet or bead has a tablet or bead corewhich may contain from about 10-70% tofacitinib; about 15-60% swellingmaterial, e.g., hydrogel; about 0-15% optional osmagent; and about 5-20%other pharmaceutical aids such as binders and lubricants. Thesemipermeable membrane coating on a tablet, preferably a celluloseacetate coating, is present at a weight corresponding to from about 2%to about 30%, preferably from 3% to 10%, of the weight of the tabletcore. The semipermeable membrane coating on a bead, preferably acellulose acetate coating, is present at a weight corresponding to fromabout 2% to about 80%, preferably from 3% to 30%, of the weight of thebead core.

A bursting coated swelling core device possesses no mechanism forsensing that the device has exited the stomach and entered the duodenum.Thus devices of this type release their tofacitinib contents at apredetermined time after entering an aqueous environment, e.g., afterbeing swallowed, as previously discussed for bursting osmotic coredevices, and the same consideration and preferences apply to makingbursting coated swelling core devices. Bursting coated swelling coredevices may be combined with immediate release devices to create adosage form that will release drug both immediately after administrationand at one or more additional predetermined times after dosing.

In a further embodiment, a “pH-triggered osmotic bursting device”,tofacitinib is incorporated into a device of the type described inallowed commonly assigned co-pending U.S. Pat. No. 5,358,502, issuedOct. 25, 1994, incorporated herein by reference. The device comprisestofacitinib and optionally one or more osmagents, surrounded at least inpart by a semipermeable membrane. The semipermeable membrane ispermeable to water and substantially impermeable to tofacitinib andosmagent. Useful osmagents are the same as those described above forbursting osmotic core devices. Useful semipermeable membrane materialsare the same as those described above for bursting osmotic core devices.A pH-trigger means is attached to the semipermeable membrane. ThepH-trigger means is activated by a pH above 5.0, and triggers the suddendelivery of the tofacitinib. In this embodiment, the pH-trigger meanscomprises a membrane or polymer coating which surrounds thesemipermeable coating. The pH-trigger coating contains a polymer whichis substantially impermeable and insoluble in the pH range of thestomach, but becomes permeable and soluble at about the pH of theduodenum, about pH 6.0.

Exemplary pH-sensitive polymers are polyacrylamides, phthalatederivatives such as acid phthalates of carbohydrates, amylose acetatephthalate, cellulose acetate phthalate, other cellulose esterphthalates, cellulose ether phthalates, hydroxypropylcellulosephthalate, hydroxypropylethylcellulose phthalate,hydroxypropylmethylcellulose phthalate, methylcellulose phthalate,polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate,sodium cellulose acetate phthalate, starch acid phthalate,styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acidpolyvinylacetate phthalate copolymer, styrene and maleic acidcopolymers, polyacrylic acid derivatives such as acrylic acid andacrylic ester copolymers, polymethacrylic acid and esters thereof, polyacrylic methacrylic acid copolymers, shellac, and vinyl acetate andcrotonic acid copolymers.

Preferred pH-sensitive polymers include shellac; phthalate derivatives,particularly cellulose acetate phthalate, polyvinylacetate phthalate,and hydroxypropylmethylcellulose phthalate; polyacrylic acidderivatives, particularly polymethyl methacrylate blended with acrylicacid and acrylic ester copolymers; and vinyl acetate and crotonic acidcopolymers. As described above cellulose acetate phthalate is availableas a latex under the tradename Aquateric® (registered trademark of FMCCorp., Philadelphia, Pa.), and acrylic copolymers are available underthe tradenames Eudragit-R® and Eudragit-L®. For appropriate applicationin this embodiment, these polymers should be plasticized utilizingplasticizers described above. The pH-trigger coating may also comprise amixture of polymers, for example cellulose acetate and cellulose acetatephthalate. Another suitable mixture comprises Eudragit-L® andEudragit-S®; the ratio of the two, and the coating thickness, definingthe sensitivity of the “trigger”, e.g., the pH at which the outerpH-trigger coating weakens or dissolves.

A pH-triggered osmotic bursting device generally operates as follows.After oral ingestion, the pH-trigger coating, which surrounds thesemipermeable coating, which in turn surrounds thetofacitinib-containing core tablet or bead, remains undissolved andintact in the stomach. In the stomach, water may or may not commencepenetration through the pH-trigger coating and the semipermeablecoating, thus starting hydration of the core, which contains tofacitiniband optional osmagent. After the device has exited the stomach and hasentered the small intestine, the pH-trigger coating rapidlydisintegrates and dissolves, and water passes through the semipermeablecoating, dissolving tofacitinib and optional osmagent within the core.As the colloidal osmotic pressure across the semipermeable coatingexceeds some threshold value, the semipermeable coating fails, and thedevice bursts, releasing tofacitinib. It is preferred that this burstingand release of tofacitinib occur at about 15 minutes or more, preferably30 minutes or more, after the pH-triggered osmotic bursting device exitsthe stomach and enters the duodenum, thus minimizing exposure of thesensitive duodenum to tofacitinib.

For a pH-triggered osmotic bursting device, the lag-time or delay-timeis controlled by the choice and amount of osmagent in the core, by thechoice of semipermeable coating, and by the thickness of thesemipermeable coating. It will be appreciated by those skilled in theart, for example, that a thicker semipermeable coating will result in alonger delay after the device has exited the stomach. A preferredpH-triggered osmotic bursting device is a bead or tablet core oftofacitinib with optional osmagent, coated with a 3-20% by weightcellulose acetate membrane, coated with a 3-20% by weight membranecomposed of about 1:1 cellulose acetate/cellulose acetate phthalate.Another preferred pH-triggered osmotic bursting device is a bead ortablet core of tofacitinib with optional osmagent, coated with a 3-20%by weight cellulose acetate membrane, coated with a 3-20% by weightmembrane comprising from about 9:1 to about 1:1 Eudragit-L®/Eudragit-S®.

Advantageously, because a pH-triggered osmotic bursting device possessesa mechanism for sensing that the device has exited the stomach,intersubject variability in gastric emptying is not significant.

In a further embodiment, a “pH-triggered bursting coated swelling core”,a tablet core or bead containing tofacitinib and a swelling material iscoated with a semipermeable coating which is further coated with apH-sensitive coating. The core composition, including choice of swellingmaterial is as described above for the bursting coated swelling coreembodiment. The choice of semipermeable coating material andpH-sensitive coating material are as described above for the“pH-triggered osmotic core” embodiment. This device is described indetail in commonly-assigned copending U.S. patent application Ser. No.08/023,227, filed Feb. 25, 1993, incorporated herein by reference.

A pH-triggered bursting swelling core embodiment generally operates asfollows. After oral ingestion, the pH-trigger coating, which surroundsthe semi-permeable coating, which in turn surrounds thetofacitinib-containing core tablet or bead, remains undissolved andintact in the stomach. In the stomach, water may or may not commencepenetration through the pH-trigger coating and the semipermeablecoating, thus starting hydration of the core, which contains tofacitiniband water-swellable material, preferably a hydrogel. When thepH-triggered bursting swelling core device exits the stomach and entersthe small intestine, the pH-trigger coating rapidly disintegrates anddissolves, and water passes through the semipermeable coating,dissolving tofacitinib and swelling the water-swellable material withinthe core. As the swelling pressure across the semipermeable coatingexceeds some threshold value, the semipermeable coating fails, and thedevice bursts, releasing tofacitinib. This bursting and release oftofacitinib occurs at about 15 minutes or more, around about 30 minutes,after the pH-triggered bursting swelling core device exits the stomachand enters the duodenum, thus minimizing exposure of the sensitiveduodenum to tofacitinib.

For the “pH-triggered bursting swelling core” device, the lag-time ordelay-time can be controlled by the choice and amount of swellingmaterial in the core, by the choice of semipermeable coating, and by thethickness of the semipermeable coating. It will be appreciated by thoseskilled in the art, for example, that a thicker semipermeable coatingwill result in a longer delay after the device has exited the stomach. ApH-triggered bursting swelling core device contains a bead or tabletcore of tofacitinib with synthetic hydrogel, preferablycarboxymethylcellulose, coated with a 3-20% by weight cellulose acetatemembrane, coated with a 3-20% by weight membrane composed of about 1:1cellulose acetate/cellulose acetate phthalate. Another pH-triggeredbursting swelling core device contains a bead or tablet core oftofacitinib with synthetic hydrogel, preferably carboxymethylcellulose,coated with a 3-20% by weight cellulose acetate membrane, coated with a3-20% by weight membrane composed of from about 9:1 to about 1:1Eudragit-L®/Eudragit-S®.

Advantageously, because a pH-triggered bursting swelling core devicepossesses a mechanism for sensing that the device has exited thestomach, intersubject variability in gastric emptying is notsignificant. pH-triggered bursting swelling core devices may be combinedwith immediate release devices to create a dosage form that will releasedrug both immediately after administration and at one or more additionalpredetermined locations in the GI tract after dosing.

A current review of this bursting technology is Journal of ControlledRelease; 134 (2009) 74-80 and herein incorporated as reference in itsentirety.

Delayed release embodiments of the invention are solid dosage forms fororal administration comprising tofacitinib and a pharmaceuticallyacceptable carrier, which release not more than 10% of theirincorporated tofacitinib into a mammal's stomach, and which release notmore than an additional 10% during the first 15 minutes after enteringsaid mammal's duodenum. The timing of release of tofacitinib in thestomach or duodenum may be tested utilizing a variety of approachesincluding, but not limited to, x-ray evaluation, nuclear magneticresonance imaging, gamma scintigraphy, or direct sampling of the gastricand duodenal contents via intubation. These tests, while possible, canbe very difficult to carry out in humans. A more convenient test for adelayed release embodiment of the current invention is a two stage invitro dissolution test.

The invention will be illustrated in the following non-limitingexamples.

EXAMPLES Example 1. Extrudable Core System Osmotic Tablet

22 mg Tablet Core

One-half of the batch quantity of sorbitol, 2663.01 grams (also seeTable 1 below), was added to a 28 L bin. The batch quantity ofCopovidone, 420.00 grams, was then added to the 28 L bin. The batchquantity of Tofacitinib, 623.98 g, was then added to the 28 L bin. Thebatch quantity of Hydroxycellulose, 560.00 grams, was then added to the28 L bin. The remaining one-half of the batch quantity of sorbitol,2663.01 grams was added to the 28 L bin. All of the components wereblended in the bin for 15 minutes at 12+/−1 RPM.

The blend was passed through a Comil rotary mill equipped with a 0.032″screen and a round edge impeller running at approximately 950 RPM. Theblend was collected in a second 28 L bin. The bin contents were blendedfor 10 minutes at 15+/−1 RPM.

Magnesium stearate, 70 g, was passed through an 850-micron mesh screenand was added to the bin and contents were blended for 5.5 minutes at12+/−1 RPM. Final blend was transferred to the hopper of a Fette rotarytablet press. Tablets were compressed using 0.2620″×0.5240″ modifiedoval tooling, to an average target weight of 400 mg+/−5%, average targetthickness of 5.35 mm+/−0.05 mm, and a target hardness of 13 kP. Tabletswere passed through a deduster and a metal detector.

TABLE 1 Composition # Material Function (%) Grams 1 Tofacitinib CitrateActive 8.914 623.98 2 Sorbitol Osmagen 76.086 5326.02 3Hydroxyethylcellulose Viscosifying 8.000 560.00 Agent 4 Kollidon VA 64Binder 6.000 420.00 (copovidone) 5 Magnesium Stearate Lubricant 1.00070.00 Core Tablet Weight — 100%   7000.00 g11 mg Tablet Core

One-half of the batch quantity of sorbitol, 2819.01 grams (also seeTable 2 below), was added to a 28 L bin. The batch quantity ofCopovidone, 420.00 grams, was then added to the 28 L bin. The batchquantity of Tofacitinib, 311.99 g, was then added to the 28 L bin. Thebatch quantity of Hydroxycellulose, 560.00 grams, was then added to the28 L bin. The remaining one-half of the batch quantity of sorbitol,2819.0 grams was added to the 28 L bin. All of the components wereblended in the bin for 15 minutes at 12+/−1 RPM.

The blend was passed through a Comil rotary mill equipped with a 0.032″screen and a round edge impeller running at approximately 950 RPM. Theblend was collected in a second 28 L bin. The bin contents were blendedfor 10 minutes at 15+/−1 RPM.

Magnesium stearate, 70 g, was passed through a 850-micron mesh screenand was added to the bin and contents were blended for 5.25 minutes at12+/−1 RPM. Final blend was transferred to the hopper of a Fette rotarytablet press. Tablets were compressed using 0.2620″×0.5240″ modifiedoval tooling, to an average target weight of 400 mg+/−5%, average targetthickness of 5.35 mm+/−0.05 mm, and a target hardness of 15 kP. Tabletswere passed through a deduster and a metal detector.

TABLE 2 Composition # Material Function (%) Grams 1 Tofacitinib CitrateActive 4.457 311.99 2 Sorbitol Osmagen 80.543 5638.01 3Hydroxyethylcellulose Viscosifying 8.000 560.00 Agent 4 Kollidon VA 64Binder 6.000 420.00 (copovidone) 5 Magnesium Stearate Lubricant 1.00070.00 Core Tablet Weight — 100%   7000.00 gTablet Coating and Drilling

4049-kilogram coating solution was prepared according to the followingsteps: First, the entire 396.0 grams of water (also see Table 3 below)and 1464.0 grams of acetone were added to a 5-Liter vessel and mixed for5 minutes. 32.4 grams of hydroxypropyl cellulose were added to themixture and mixed for 5 minutes. 48.6 grams of cellulose acetate wereadded to the mixture and mixed for 5 minutes. The remaining 2108 gramsof acetone were added to the mixture and mixed for 3 hours. Thisprocedure created a 2% solids (w/w) solution.

TABLE 3 coat Batch Composition of duration 1 % in mg/ w/w Quantitycoated tablet coating tablet (%) (Grams) 1. Tofacitinib Citrate TabletCore — 400 — — 2. Cellulose Acetate (Type 398-10)  1.2% 14.4 3.6 48.6 3.Hydroxypropyl Cellulose  0.8% 9.6 2.4 32.4 (Klucel EF) 4. Acetone 88.2%(1058.4) — 3572.0 5. Purified water  9.8% (117.6)  396.0 Total Weight 100% 424 6.0 4049.0

900 grams of the 400 mg weight oval tablets were coated in a VectorLDCS-5 with a 1.5-Liter semi-perforated pan operating at 20 rpm and anairflow of 30 CFM having an exhaust temperature of 40 deg C. The 2%solids (w/w) solution was applied until the wet weight gain reached alevel of 62%. The tablets were then removed from coating pan and driedat 40 C for 16 hours.

A single hole (1000 micron) was drilled in the end of the band of theoval tablet. The hole can be drilled either by mechanical means or vialaser ablation. A coating of 6% provided the following release in pH 6.8media, paddles at 50 rpm based on Dissolution test 1 (Table 4):

TABLE 4 Time 11 mg tablet % 22 mg tablet % (hr) Drug Dissolved DrugDissolved 1 11 15 2.5 55 61 5 87 92

Example 2. 200 mg Extrudable Core System Osmotic Tablets withAcetone:Methanol Coating Solution

11 mg Tablet Core

One-half of the batch quantity of sorbitol, 38.014 kilograms (also seeTable 5 below), was added to a 300 L bin. The batch quantity ofCopovidone, 6.00 kilograms, was then added to the 300 L bin. The batchquantity of Tofacitinib, 8.914 kilograms, was then added to the 300 Lbin. The batch quantity of Hydroxycellulose, 8.00 kilograms, was thenadded to the 300 L bin. The remaining one-half of the batch quantity ofsorbitol, 38.014 grams was added to the 300 L bin. All materials wereadded via a vacuum transfer system and passed through a Comil rotarymill equipped with a 0.032″ screen and a round edge impeller running atapproximately 1400 RPM. All of the components are blended in the bin for20 minutes at 12+/−1 RPM.

The blend was passed through a Comil rotary mill equipped with a 0.032″screen and a round edge impeller running at approximately 1400 RPM. Theblend was collected in a second 300 L bin. The bin contents were blendedfor 20 minutes at 12+/−1 RPM.

Magnesium stearate, 1.00 kilograms, was passed through a 850-micron meshscreen and was added to the bin and contents are blended for 5 minutesat 12+/−1 RPM. Tablets were compressed using 0.2080″×0.4160″ modifiedoval tooling on a Manesty Mark IV rotary tablet press, to an averagetarget weight of 200 mg+/−5%, average target thickness of 4.17 mm+/−0.05mm, and a target hardness of 10 kP. Tablets were passed through adeduster and a metal detector.

TABLE 5 Composition 100 kg # Material Function (%) Batch 1 TofacitinibCitrate Active 8.914  8.914 2 Sorbitol Osmagen 76.086  76.086 3Hydroxyethylcellulose Viscosifying 8.000 8.00 Agent 4 Copovidone Binder6.000 6.00 5 Magnesium Stearate Lubricant 1.000 1.00 Core Tablet Weight— 100%  100.00 kg 22 mg Tablet Core

One-half of the batch quantity of sorbitol, 33.086 kilograms (also seeTable 6 below), was added to a 300 L bin. The batch quantity ofColloidal Silicon Dioxide, 1.00 kg, was then added to the 300 L bin. Thebatch quantity of Copovidone, 6.00 kilograms, was then added to the 300L bin. The batch quantity of Tofacitinib, 8.914 kilograms, was thenadded to the 300 L bin. The batch quantity of Hydroxycellulose, 8.00kilograms, was then added to the 300 L bin. The remaining one-half ofthe batch quantity of sorbitol, 33.086 grams was added to the 300 L bin.All materials were added via a vacuum transfer system and passed througha Comil rotary mill equipped with a 0.032″ screen and a round edgeimpeller running at approximately 1400 RPM. All the components wereblended in the bin for 20 minutes at 12+/−1 RPM.

The blend was passed through a Comil rotary mill equipped with a 0.032″screen and a round edge impeller running at approximately 1400 RPM. Theblend was collected in a second 300 L bin. The bin contents were blendedfor 20 minutes at 12+/−1 RPM.

Magnesium stearate, 1.00 kilograms, was passed through a 850-micron meshscreen and was added to the bin and contents are blended for 5 minutesat 12+/−1 RPM. Tablets were compressed using 0.2080″×0.4160″ modifiedoval tooling on a Manesty Mark IV rotary tablet press, to an averagetarget weight of 200 mg+/−5%, average target thickness of 4.17 mm+/−0.05mm, and a target hardness of 11 kP. Tablets were passed through adeduster and a metal detector.

TABLE 6 Composition 100 kg # Material Function (%) Batch 1 TofacitinibCitrate Active 17.828  17.828  2 Sorbitol Osmagen 66.172  66.172  3Hydroxyethylcellulose Viscosifying 8.000 8.00 Agent 4 Copovidone Binder6.000 6.00 5 Colloidal Silicon Glidant 1.000 1.00 Dioxide 6 MagnesiumStearate Lubricant 1.000 1.00 Core Tablet Weight — 100%  100.00 kg 

The 750-kilogram coating solution was prepared according to thefollowing steps (see also Table 7): First, the entire 147.0 kilograms ofmethanol and 580.5 grams of acetone were added to a 250-gallon vessel.13.5 kilograms of cellulose acetate were added to the mixture. 9.0kilogram of hydroxypropyl cellulose were added to the mixture. Thecontents of the container were mixed for 1 hour. This procedure createda 3% solids (w/w) solution.

TABLE 7 coat Batch Composition of coated % in w/w Quantity 200 mgWtablet coating mg/tablet (%) (kilograms) 1. Tofacitinib Citrate Tablet —200   — — Core 2. Cellulose Acetate  1.8%  7.9 4.0  13.5 (Type 398-10)3. Hydroxypropyl Cellulose  1.2%  5.3 2.6  9.0 (Klucel EF) 4. Methanol19.6%  (86.2) — 147.0 5. Acetone 77.4% (340.6) — 580.5 Total Weight 100% 213.2 6.6 750.0

250 kilograms of the 200 mg weight oval tablets were coated in a VectorHC-130 operating at 8 rpm and an airflow of 1000 CFM having an exhausttemperature of 28 deg C. The 3% solids (w/w) solution was applied untilthe wet weight gain reached a level of 6.8%. The tablets were thenremoved from the coating pan and dried at 45 C for 24 hours.

A single hole (600 micron) was drilled in the end of the band of theoval tablet. The hole can be drilled either by mechanical means or vialaser ablation. A coating of 6.6% provided the following release in pH6.8 media, paddles at 50 rpm based on Dissolution test 1 (Table 8):

TABLE 8 11 mg tablet % 22 mg tablet % Time (hr) Drug Dissolved DrugDissolved 1 11 10 2.5 55 55 5 85 82

Example 3. 200 mg Extrudable Core System Osmotic Tablets CelluloseAcetate and Polyethylene Gycol Coating Membrane

11 mg and 22 mg tofacitinib sustained release tablet cores were preparedas described in Example 2.

The 1200-gram coating solution was prepared according to the followingsteps (see also Table 9): First, 60 grams of water and 19.2 grams ofpolyethylene gycol were added to a 5-liter vessel and stirred until thesolution was clear. 60 grams of methanol and 0.504 grams of BHA wereadded to the solution and stirred until clear. 1031.496 grams of acetoneand 28.8 grams of cellulose acetate were added to the mixture. Thecontents of the container were mixed for 3 hours. This procedure createda 4% solids (w/w) solution.

TABLE 9 # Material Composition (%) Grams 1 Cellulose Acetate (Type398-10) 2.400% 28.8 2 Polyethylene Glycol (PEG 3350) 1.600% 19.2 3Butylated Hydroxyanisole (BHA) 0.042% 0.504 4 Purified Water 5.000% 60.05 Methanol 5.000% 60.0 6 Acetone 85.958%  1031.496   100%

240 grams of the 200 mg weight oval tablets were coated in a VectorLDCS-5 operating at 30 rpm and an airflow of 40 CFM having an exhausttemperature of 28 deg C. The 3% solids (w/w) solution was applied untilthe wet weight gain reached a level of 9.2%. The tablets were thenremoved from the coating pan and dried at 40 C for 16 hours.

A single hole (600 micron) was drilled in the end of the band of theoval tablet. The hole can be drilled either by mechanical means or vialaser ablation. A coating of 9% provides the following release in pH 6.8media, paddles at 50 rpm based on Dissolution test 1 (Table 10):

TABLE 10 11 mg tablet % 22 mg tablet % Time (hr) Drug Dissolved DrugDissolved 1 28 30 2.5 72 70 5 92 90

Example 4. Hydrophilic Matrix Controlled Release Tablet

The metal surfaces of a 10 L bin were pre-coated by adding the batchquantity (also see Table 11 below) 1484.85 g of Lactose Fast Flo 316 andblending for 2 minutes at 12+/−1 RPM. The batch quantity of Tofacitinib,171.15 g, was added to the 10 L bin and folded into the lactosemonohydrate. The Tofacitinib container was rinsed with some of thelactose monohydrate from the 10 L bin. The batch quantity ofHypromellose, 720 g, was added to the 10 L bin. All of the componentswere blended in the bin for 10 minutes at 12+/−1 RPM.

The blend was passed through a Comil rotary mill equipped with a 0.032″screen and a round edge impeller running at approximately 1400 RPM. Theblend was collected in a second 10 L bin. The bin contents were blendedfor 10 minutes at 12+/−1 RPM.

Intragranular magnesium stearate, 6 g, was added to the bin and blendedfor 3 minutes at 12+/−1 RPM. The lubricated blend was processed througha Gerteis roller compactor equipped with knurled rollers, side rims, andan inline oscillating mill containing a pocket rotor and a 1-mm raspingplate. The target ribbon solid fraction was 0.7 (0.67-0.73) and granuleswere collected in the initial 10 L bin.

Extragranular magnesium stearate, 18 g, was added to the bin andcontents were blended for 3 minutes at 12+/−1 RPM. Final blend wasaffixed above a Kilian T-100 rotary tablet press. Tablets werecompressed using 13/32″ SRC tooling, to an average target weight of 500mg+/−5% and a target hardness of 15 kP. Tablets were passed through adeduster and a metal detector.

TABLE 11 22 mg Tofacitinib hydrophilic matrix tablet composition; Totaltablet weight 500 mg Ingredient Function % Composition Grams TofacitinibCitrate Active ingredient  7.1% 171.15 Methocel K100LV CR Polymer, gelformer   30% 720.00 Premium Grade providing controlled release LactoseMonohydrate, Filler 61.9% 1484.85 Fast Flo 316 Magnesium stearate,Lubricant 0.25% 6.00 vegetable grade (IG) Magnesium stearate, Lubricant0.75% 18.00 vegetable grade (EG) Total  100% 2400.00

The compressed tablets provide the following release in pH 6.8 media,paddles at 50 rpm based on Dissolution test 1 (Table 12).

TABLE 12 Time (hr) % Drug Dissolved 1 24 2.5 47 5 76

Example 5. 20 mg Bilayer Osmotic Tablet

The batch quantities of Tofacitinib and Polyethylene Oxide N80 (see alsoTable 13) were passed through a 30 mesh screen and added to a 500 ccamber bottle. The blend was mixed for 10 minutes with a Turbula bottleblender. 0.2 grams of magnesium stearate was passed through a 30 meshscreen and added to the bottle of active blend and mixed for 3 minutes.

The batch quantities of polyethylene oxide (coagulant grade), blue lakedye, and sodium chloride were passed through a 20 or 30 mesh screen andadded in that order to a 500 cc bottle. The blend was mixed for 10minutes with a Turbula bottle blender. 0.5 grams of magnesium stearatewas passed through a 30 mesh screen and added to the bottle of swellerlayer and mixed for 3 minutes.

Tablets were compressed using 9-mm standard round convex tooling, to anaverage target weight of 400 mg+/−5%, average target thickness of 7mm+/−0.05 mm, and a target hardness of 15 kP.

TABLE 13 Batch Quantity Quantity Grade: (mg)/unit: % (grams) ActiveLayer Components: Tofacitinib Citrate 33.333 12.5% 5.0 PolyethyleneOxide WSR NF 232 87.0% 34.8 N80 Grade Magnesium Stearate^(e) NF/EP 1.333 0.5% 0.2 266.667 100.0%  40 Sweller Layer Components: PolyethyleneOxide NF 86 64.5% 64.5 Coagulant Grade^(a) Sodium Chloride^(b) USP/EP46.4 34.8% 34.8 FD&C Blue No2 Lake Dye^(d) Food 0.267  0.2% 0.2Magnesium Stearate^(e) NF/EP 0.667  0.5% 0.5 133.333 100.0%  100.0

The coating solution was prepared according to the following steps (seealso Table 14 below): First, the entire 194.6 grams of water and 800grams of acetone were added to a 5-Liter vessel and mixed for 5 minutes.24 grams of hydroxypropyl cellulose were added to the mixture and mixedfor 5 minutes. 36 grams of cellulose acetate were added to the mixtureand mixed for 5 minutes. The remaining 946.3 grams of acetone were addedto the mixture and mixed for 3 hours. This procedure created a 3% solids(w/w) solution.

TABLE 14 mg/tablet coat Batch % in 6% wt w/w Quantity Composition ofcoated tablet coating gain (%) (grams) 1. Tofacitinib Citrate BilayerCore — 400   — — Tablet Core 2. Cellulose Acetate (Type 398-10) 1.8%14.4 3.6% 36.0 3. Hydroxypropyl Cellulose 1.2%  9.6 2.4% 24.0 (KlucelEF) 4. Acetone 87.3%  (698.4)  — 1746.3 5. Purified water 9.7% (77.6) —194.6 Total Weight  100%  424     6% 2000.9

250 grams of the 400 mg weight SRC tablets were coated in a VectorLDCS-5 with a 0.5-Liter semi-perforated pan operating at 30 rpm and anairflow of 30 CFM having an exhaust temperature of 40 deg C. The 3%solids (w/w) solution was applied until the wet weight gain reached alevel of 6.2%. The tablets were then removed from coating pan and driedat 40 C for 16 hours.

A single hole (1000 micron) was drilled in the end of the band of theoval tablet. The hole can be drilled either by mechanical means or vialaser ablation. The target coating of 6% provided the following releasein pH 6.8 media, paddles at 50 rpm based on Dissolution test 1 (Table15):

TABLE 15 6% Weight Gain Time (hr) (% Drug Dissolved) 1 6 2.5 42 5 95

Example 6. 11 mg Bilayer Osmotic Tablet

The batch quantity of Polyethylene Oxide N80 (active layer) (see alsoTable 16) was passed through a 30 mesh screen. The large particles thatremained on the screen were discarded. Polyethylene Oxide was added to a500 cc amber bottle and hand blended to coat the inside of the bottle.The batch quantity of Tofacitinib was added and mixed for 10 minuteswith a Turbula bottle blender. 1.0 gram of magnesium stearate was addedto the bottle of active blend and mixed for 3 minutes.

The batch quantity of Polyethylene oxide Coagulant grade (sweller layer)and sodium chloride were passed through 30 mesh screen. Polyethyleneoxide, the batch quantity of microcrystalline cellulose, the batchquantity of blue lake dye and sodium chloride powder were added in thatorder to a 950 cc bottle. The blend was mixed for 10 minutes with aTurbula bottle blender. 1.0 gram of magnesium stearate was added to thebottle of sweller layer and mixed for 3 minutes.

Bilayer tablets are compressed using 9/32 inch standard round convextooling, to an average target weight of 180.0 mg+/−5% and an averagetarget thickness of 5.0 mm+/−0.1 mm.

TABLE 16 Batch Quantity Quantity Grade: (mg)/unit: % (grams) ActiveLayer Components: Tofacitinib Citrate 17.76 14.80 14.80 PolyethyleneOxide NF 101.04 84.20 84.20 WSR N80 Grade^(a) Magnesium Stearate^(e)NF/EP 1.20 1.00 1.00 120.00 100.00 100.00 Sweller Layer Components:Polyethylene Oxide NF 32.52 54.20 108.40 Coagulant Grade^(a)Microcrystalline Cellulose PhEur/NF 12.00 20.00 40.00 SodiumChloride^(b) USP/EP 15.00 25.00 50.00 FD&C Blue No2 Lake Dye^(d) Food0.18 0.30 0.60 Magnesium Stearate^(e) NF/EP 0.30 0.50 1.00 60.00 100.0%200.00

The coating solution was prepared according to the following steps (seealso Table 17): First, 180.0 grams of water was added to 48.6 grams ofPEG 3350 in 4 L mixing vessel and mixed or swirled by hand until the PEGwas entirely dissolved. Secondly, 131.4 g of cellulose acetate was addedto the 4 L mixing vessel containing the PEG-water solution. The CA wasdisbursed as a slurry or wet cake. While using the 4 L mixing vesselequipped with a rotating impeller, 2,640.0 grams of acetone was added tothe PEG-water-CA mixture. The contents of the mixing vessel wereagitated until all solids were dissolved.

TABLE 17 # Material Composition (%) Grams 1 Cellulose Acetate 4.38%131.4 2 Polyethylene Glycol 3350 with 1.62% 48.6 100 ppm BHT (PEG 3350)3 Acetone ⁽¹⁾ 88.00%  2640.0 4 Purified Water ⁽¹⁾ 6.00% 180.0 Total100.00%  3000.0 Component Coating Solution % Wt mg/tablet TofacitinibCitrate Bilayer Core — 180.00 Tablet Core Coating Composition CelluloseAcetate 4.38% 17.08 Polyethylene Glycol 3350 with 1.62% 6.32 100 ppm BHT(PEG 3350) Acetone ⁽¹⁾ 88.00%  343.20 Purified Water ⁽¹⁾ 6.00% 23.40Total 100.00%  203.40 ⁽¹⁾ Included for Coating Compositional Purposes,Not Present in Final Dosage Form

250 grams of the 180 mg bilayer tablet cores were coated in a VectorLDCS-5 with a 0.5 liter fully perforated coating pan operating at 30 rpmand an airflow of 35 CFM having an exhaust temperature of 32 deg C. The6% solids (w/w) solution was applied until an in-process coating weightgain of 25.2 mg per tablets was achieved. The tablets were then removedfrom coating pan and dried at 40 C for 16 hours.

A single delivery port with a diameter of 1.0 mm was formed through thecoating membrane centered on the face of the drug layer side of thebilayer tablet. The delivery port can be formed either by mechanicalmeans or via laser ablation. The target coating level of 23.4 mg or 13%of the target bilayer core weight provided a controlled release drugdelivery exhibiting 80% of the drug delivered at 3.5 hours in pH 6.8media, paddles at 50 rpm based on Dissolution test 1. Additionaldissolution data is given in Table 18.

TABLE 18 Time (hours) % Release 1.0 13 2.5 55 5.0 96

Example 7. 11 mg A Bilayer Osmotic Tablet with Antioxidants

The formulation of Example 7 was made as follows (see also Table 19):Polyethylene oxide N80 was passed through a 30 mesh screen. The largeparticles of polyethylene oxide N80 that remain on the screen werediscarded. Separately, the primary particle size of the sodiummetabisulfite and butylated hydroxyanisole was reduced using a mortarand pestle. One-fourth the batch amount of polyethylene oxide wascombined with the batch amounts of sodium metabisulfite and butylatedhydroxyanisole and added to a 950 cc amber glass bottle and mixed for 5minutes in a Turbula bottle blender. The remaining polyethylene oxideN80 and batch amount of tofacitinib citrate was added to the 950 ccamber glass bottle and mixed in a Turbula bottle blender for 10 minutes.The blend was passed through a mini Co-mil using a 0.8 mm screen size toenhance mixing and distribution of components. The blend was then mixedfor an additional 10 minutes in a Turbula bottle blender. The batchamount of magnesium stearate was then added to the previous mixture inthe 950 cc amber glass bottle and was mixed for 3 minutes in a Turbulabottle blender.

Polyethylene oxide Coagulant grade and sodium chloride were passedthrough 30 mesh screen and the large particles that remained on thescreen were discarded. Separately, the primary particle size of thesodium metabisulfite and butylated hydroxyanisole was reduced using amortar and pestle. One-half the batch amount of polyethylene oxide wascombined with the batch amounts of sodium metabisulfite and butylatedhydroxyanisole and added to a 950 cc amber glass bottle and mixed for 5minutes in a Turbula bottle blender. The remaining amount ofpolyethylene oxide Coagulant grade, microcrystalline cellulose, bluelake dye and sodium chloride powder were added in that order to a 950 ccamber glass bottle and mixed for 10 minutes with a Turbula bottleblender. The blend was passed through a mini Co-mil using a 0.8 mmscreen size to enhance mixing and distribution of components. 1.0 gramof magnesium stearate was added to the bottle and mixed for 3 minutes.

Bilayer tablets were compressed using 9/32 inch standard round convextooling, to an average target weight of 180.0 mg+/−5% and an averagetarget thickness of 5.0 mm+/−0.1 mm.

TABLE 19 Unit Quantity Batch Quantity % Weight (mg/tablet) (grams)Active Layer Components Tofacitinib Citrate 14.80 17.76 29.61Polyethylene Oxide 79.30 95.16 158.59 (Polyox WSR N80) SodiumMetabisulfite 4.67 5.60 9.33 Butylated Hydroxyanisole 0.23 0.28 0.47Magnesium Stearate 1.00 1.20 2.00 Total 100.00 120.00 200.00 SwellerLayer Components: Polyethylene Oxide 51.67 31.00 103.33 (Polyox WSRCoagulant) Microcrystalline Cellulose 20.00 12.00 40.00 Sodium Chloride25.00 15.00 50.00 Sodium Metabisulfite 2.41 1.45 4.82 ButylatedHydroxyanisole 0.12 0.07 0.24 FD&C Blue No2 Lake 0.30 0.18 0.60Magnesium Stearate 0.50 0.30 1.00 Total 100.00 60.00 200.00

The coating solution was prepared according to the following steps (seealso Table 20): First, 150.0 grams of water was added to 40.5 grams ofPEG 3350 in 4 L mixing vessel and mixed or swirled by hand until the PEGwas entirely dissolved. Secondly, 109.5 g of cellulose acetate was addedto the 4 L mixing vessel containing the PEG-water solution. The CA wasdisbursed as a slurry or wet cake. While using the 4 L mixing vesselequipped with a rotating impeller, 2198.1 grams of acetone was added tothe PEG-water-CA mixture. The contents of the mixing vessel wereagitated until all solids are dissolved.

TABLE 20 # Material Composition (%) Grams 1 Cellulose Acetate  4.38%109.5 2 Polyethylene Glycol 3350 with 100  1.62% 40.50 ppm BHT (PEG3350) 3 Sodium Metabisulfite  0.064% 1.60 4 Butylated Hydroxyanisole 0.012% 0.31 5 Acetone⁽¹⁾  87.92% 2198.1 6 Purified Water⁽¹⁾  6.00%150.0 Total 100.00% 2500.0

250 grams of the tofacitinib bilayer tablet cores were coated in aVector LDCS-5 with a 0.5 liter fully perforated coating pan operating at30 rpm and an airflow of 35 CFM having an exhaust temperature of 32 degC. The 6% solids (w/w) solution was applied until an in-process coatingweight gain of 25.2 mg per tablets was achieved. The tablets were thenremoved from coating pan and dried at 40 C for 16 hours.

A single delivery port with a diameter of 1.0 mm was formed through thecoating membrane centered on the face of the drug layer side of thebilayer tablet. The delivery port was formed either by mechanical meansor via laser ablation. The target coating level of 23.7 mg or 13% of thetarget bilayer core weight provides a controlled release drug deliverycorresponding to 80% of the drug delivered at 2.8 hours in pH 6.8 media,paddles at 50 rpm based on Dissolution test 1. Additional dissolutiondata is given in Table 21.

TABLE 21 Time (hours) % Release 1.0 17 2.5 73 5.0 98

Example 8. 22 mg Bilayer Osmotic Tablet

The formulation of Example 8 was made as follows (see also Table 22):The batch quantity of Polyethylene Oxide N80 was passed through a 30mesh screen. The large particles that remained on the screen werediscarded. Polyethylene Oxide N80 was added to a 500 cc amber bottle andhand blended to coat the inside of the bottle. The batch quantity ofTofacitinib was added and mixed for 10 minutes with a Turbula bottleblender. 1.0 gram of magnesium stearate was added to the bottle ofactive blend and mixed for 3 minutes.

The batch quantity of Polyethylene oxide Coagulant grade and sodiumchloride were passed through 30 mesh screen. Polyethylene oxide, thebatch quantity of microcrystalline cellulose, the batch quantity of bluelake dye and sodium chloride powder were added in that order to a 950 ccbottle. The blend was mixed for 10 minutes with a Turbula bottleblender. 1.0 gram of magnesium stearate was added to the bottle ofsweller layer and mixed for 3 minutes.

Tablets were compressed using 5/16 inch standard round convex tooling,to an average target weight of 250.0 mg+/−5% and an average targetthickness of 5.6 mm+/−0.1 mm.

TABLE 22 Batch Active Layer Quantity Quantity Components: Grade:(mg)/unit: % (grams) Tofacitinib Citrate 35.53  21.28% 21.28Polyethylene Oxide NF 129.80  77.72% 77.72 WSR N80 Grade^(a) MagnesiumStearate^(e) NF/EP 1.67  1.0% 1.00 167.00 100.0% 100.00 Batch SwellerLayer Quantity Quantity Components: Grade: (mg)/unit: % (grams)Polyethylene Oxide NF 44.99 54.20 108.40 Coagulant Grade^(a)Microcrystalline Cellulose PhEur/NF 16.60 20.00 40.00 SodiumChloride^(b) USP/EP 20.75 25.00 50.00 FD&C Blue No2 Lake Dye^(d) Food0.25 0.30 0.60 Magnesium Stearate^(e) NF/EP 0.42 0.50 1.00 83.00 100.0%200.00

The coating solution was prepared according to the following steps (seealso Table 23): First, 180.0 grams of water was added to 48.6 grams ofPEG 3350 in 4 L mixing vessel and mixed or swirled by hand until the PEGwas entirely dissolved. Secondly, 131.4 g of cellulose acetate was addedto the 4 L mixing vessel containing the PEG-water solution. The CA wasdispersed as a slurry or wet cake. While using the 4 L mixing vesselequipped with a rotating impeller, 2,640.0 grams of acetone was added tothe PEG-water-CA mixture. The contents of the mixing vessel wereagitated until all solids were dissolved.

TABLE 23 # Material Composition (%) Grams 1 Cellulose Acetate  4.38%131.4 2 Polyethylene Glycol 3350 with 100  1.62% 48.6 ppm BHT (PEG 3350)3 Acetone  88.00% 2640.0 4 Purified Water  6.00% 180.0 Total 100.00%3000.0 Coating Solution Component % Wt mg/tablet Tofacitinib CitrateBilayer — 250.00 Core Tablet Core Cellulose Acetate  4.38% 20.08Polyethylene Glycol 3350  1.62% 7.43 with 100 ppm BHT (PEG 3350)Acetone⁽¹⁾  88.00% 403.33 Purified Water⁽¹⁾  6.00% 27.5 Total 100.00%277.50 ⁽¹⁾Included for Coating Compositional Purposes, Not Present inFinal Dosage Form

250 grams of the bilayer tablet cores were coated in a Vector LDCS-5with a 0.5-Liter fully perforated coating pan or drum operating at 30rpm and an airflow of 35 CFM having an exhaust temperature of 32 deg C.The 6% solids (w/w) solution was applied until an in-process coatingweight gain of 30.0 mg per tablets was achieved. The tablets were thenremoved from coating pan and dried at 40 C for 16 hours.

A single delivery port with a diameter of 1.0 mm was formed through thecoating membrane centered on the face of the drug layer side of thebilayer tablet. The delivery port can be formed either by mechanicalmeans or via laser ablation. The target coating level of 27.5 mg or 11%of the target bilayer core weight provided a controlled release drugdelivery exhibiting 80% of the drug delivered at 3.7 hours in pH 6.8media, paddles at 50 rpm based on Dissolution test 1. Additionaldissolution data is given in Table 24.

TABLE 24 Time (hours) % Release 1.0 11 2.5 53 5.0 90

Example 9. 20 mg AMT Formulation

Formulate Example 9—as follows (see also Table 25). Pass the batchquantities of Tofacitinib, Mannitol, Microcrystalline Cellulose, andDibasic Calcium Phosphate through a 30 mesh screen and add to a 500 ccamber bottle. Mix the blend for 10 minutes with a Turbula bottleblender. Pass 0.3 grams of magnesium stearate through a 30 mesh screenand add to the bottle of active blend and mix for 3 minutes.

Compress the blend into compacts having a solid fraction of ˜0.70. Millthe compacts to form a granulation. Pass 0.2 grams of magnesium stearatethrough a 30 mesh screen and add to the bottle of active granulation andmix for 3 minutes.

Compress tablets using 9-mm standard round convex tooling, to an averagetarget weight of 400 mg+/−5%, average target thickness of 7 mm+/−0.05mm, and a target hardness of 15 kP.

TABLE 25 Batch Quantity Quantity Sweller Layer Components: Grade:(mg)/unit: % (grams) Tofacitinib Citrate 33.33 8.33% 3.33 Mannitol 2080NF/EP 140.00  35% 14 Microcrystalline Cellulose NF/EP 60.00  15% 6Dibasic Calcium Phosphate NF/EP 161.67 40.42%   16.17 MagnesiumStearate^(e) NF/EP 3.00 0.75%  0.3 Magnesium Stearate^(e) NF/EP 2.000.50%  0.2 400.00 100.0%  40

Prepare the coating solution according to the following steps (see alsoTable 26): First, add 115 grams of water and 150 grams of acetone to a2-Liter vessel and mix for 5 minutes. Add 12 grams of hydroxypropylcellulose to the mixture and mix for 5 minutes. Add 28 grams ofcellulose acetate to the mixture and mix for 5 minutes. Add theremaining 195 grams of cellulose acetate to the mixture and mixed for 3hours. This procedure creates a 8% solids (w/w) solution.

TABLE 26 mg/tablet Composition of duration 1 coated tablet % in coating7.5% wt gain 1. Tofacitinib Citrate Tablet Core — 400 2. CelluloseAcetate (Type 398-10) 5.6% 21.0 3. Hydroxypropyl Cellulose (Klucel EF)2.4% 9.0 4. Acetone 69.0% (258.8) 5. Purified water 23.0% (86.2) TotalWeight 100% 430

Coat 250 grams of the 400 mg weight SRC tablets in a Vector LDCS-5 witha 0.5-Liter semi-perforated pan operating at 30 rpm and airflow of 30CFM having an exhaust temperature of 40 deg C., Spray the 6% solids(w/w) solution until the wet weight gain reached a level of 7.5%. Removethe tablets from the coating pan and dry at 40 C for 16 hours.

Example 10. 20 mg Bilayer Osmotic Capsule

Pre-Mix

98.94 grams of polyethylene oxide (Polyox WSR N80 LEO) and 1.06 grams ofmagnesium stearate were passed through a 30-mesh sieve and added to a250 ml amber bottle. The blend was mixed using a Turbula mixer (ModelT2F) operating at 49 cycles/min for 2 minutes.

Active Layer—600 mg Weight

283.71 mg of the Pre-mix was added to a 1 dram glass vial and shaken byhand to pre-coat the inside of the glass vial. 32.57 mg of tofacitinibcitrate was passed through a 20 or 30 mesh sieve and added to the 1 dramglass vial. An additional 283.71 mg of the Pre-mix was then added to the1 dram glass vial. The contents of the glass vial were then blendedusing a Turbula mixer (Model T2F) operating at 49 cycles/min for 5minutes. The blend was then transferred to a Natoli single-stationhydraulic tablet press and compressed to a target thickness of 15.6 mmusing 5.500″ B-type 0.3051″ Modified Ball Upper Punch and a 4.755″B-type 0.3051″ Flat Face Bevel Edge Lower Punch.

Sweller Layer—300 mg Weight

The sweller layer for the formulation of Example 10 was made as follows(see also Table 27): The batch quantities of polyethylene oxideCoagulant grade, blue lake dye, sodium chloride and microcrystallinecellulose were passed through a 20 or 30 mesh screen added in that orderto a 10-Liter Bin blender. The contents of the blender were mixed for 10minutes of 12 rpm. The blend was then passed blend through a Comil 197Swith a round impeller and 0.055″ round screen operating at 1000 rpm. Thebatch quantity of magnesium stearate was added to the middle of thede-lumped blend in the bin blender. The contents of the blender weremixed for 5 minutes of 12 rpm. The blend was then transferred to aKilian T-100 rotary tablet press and compressed to a target weight of300 mg and a target thickness of 6.65 mm using 5.500″ B-type 0.3051″Modified Ball Upper Punch and a 4.755″ B-type 0.3051″ Flat Face BevelEdge Lower Punch.

TABLE 27 Batch Quantity Quantity Component: Grade: (mg)/unit: % (grams)Polyethylene Oxide NF 154.50 51.5% 2060.00 Coagulant Grade^(a) SodiumChloride^(b) USP/EP 104.40 34.8% 1392.00 Microcrystalline Cellulose^(c)NF/EP 39.00 13.0% 520.00 FD&C Blue No2 Lake Dye^(d) Food 0.60  0.2% 8.00Magnesium Stearate^(e) NF/EP 1.50  0.5% 20.00 300.00 100.0%  4000.00Capsule Shell

2.5 kg of pre-coating solution was prepared by combining 25 grams ofpolysorbate 80 with 2475 grams of acetone and mixing for 10 minutes oruntil dissolved to yield a 1% (w/w) solution.

15 kg of functional coating solution was prepared according to thefollowing steps (see also Table 28): First, the entire 375 grams ofwater and 120 grams of PEG 3350 were added to a suitable vessel andmixed. 14,325 grams of acetone were added to the mixture and mixed. 180grams of cellulose acetate were added to the mixture and mixed until auniform solution was obtained. This procedure created a 2% solids (w/w)solution.

TABLE 28 Batch Composition of % in mg in Quantity capsule shells coatingmg in cap body (grams) 1. Cellulose Acetate 1.2% 58.5 55.5 180 (Type398-10) 2. Polyethylene 0.8% 39.0 37.0 120 Glycol 3350 3. Acetone 95.5%(4655.6) (4416.9) (14,325) 4. Purified water 2.5%  (121.9)  (115.6)  (375) Total Weight 100% 97.5 92.5 15,000

1 kg of HDPE capsule molds (either caps or bodies) were coated in aVector LDCS-5 with a 1.5-Liter semi-perforated pan operating at 18 rpmand an airflow of 40 CFM having an exhaust temperature of 40 deg C.After briefly coating the molds with the 1% w/w pre-coating solution,the functional 2% solids (w/w) coating solution was sprayed at a rate of20 grams/min with atomizing air pressure of 10 psi and a gun-to-beddistance of 3 inches until the wet weight gain reached a level of 12.5%.The capsule molds were then removed from coating pan and dried at 40 Cfor 24 hours. The capsule shells were then removed from the molds andtrimmed.

A single hole (2000 microns) was drilled in the end of the capsulebodies. The hole can be drilled either by mechanical means or via laserablation

Assembly

The Active Layer was inserted into the half of the capsule shell withthe pre-drilled hole. The Sweller Layer was inserted into the same halfof the capsule shell, flat side first, to be flush against the activelayer. These components were inserted into the other half of the capsuleshell to close the capsule. When prepared and combined in this manner,these components provided the following release in pH 6.8 media, paddlesat 50 rpm based on Dissolution test 1 (Table 29)

TABLE 29 Time (hr) % Drug Dissolved 1 4 2.5 25 5 6580% of tofacitinib was dissolved in about 6 hours in Dissolution test 1.

Example 11. 20 mg Bilayer Osmotic Capsule

Pre-Mix

98.94 grams of polyethylene oxide (Polyox WSR N80 LEO) and 1.06 grams ofmagnesium stearate were passed through a 30-mesh sieve and added to a250 ml amber bottle. The blend was mixed using a Turbula mixer (ModelT2F) operating at 49 cycles/min for 2 minutes.

Active Layer—600 mg weight

283.71 mg of the Pre-mix was added to a 1 dram glass vial and shaken byhand to pre-coat the inside of the glass vial. 32.57 mg of tofacitinibcitrate was passed through a 20 or 30 mesh sieve and added to the 1 dramglass vial. 283.71 mg of the Pre-mix was then added to the 1 dram glassvial. The contents of the glass vial were then blended using a Turbulamixer (Model T2F) operating at 49 cycles/min for 5 minutes. The blendwas then transferred to a Natoli single-station hydraulic tablet pressand compressed to a target thickness of 15.6 mm using a 5.500″ B-type0.3051″ Modified Ball Upper Punch and a 4.755″ B-type 0.3051″ Flat FaceBevel Edge Lower Punch.

Sweller Layer

The sweller layer for the formulation of Example 11 was made as follows(see also Table 30). The batch quantities of polyethylene oxideCoagulant grade, blue lake dye, sodium chloride and microcrystallinecellulose were passed through a 20 or 30 mesh screen added in that orderto a 10-Liter Bin blender. The contents of the blender were mixed for 10minutes of 12 rpm. The blend was then passed blend through a Comil 197Swith a round impeller and 0.055″ round screen operating at 1000 rpm. Thebatch quantity of magnesium stearate was added to the middle of thede-lumped blend in the bin blender. The contents of the blender weremixed for 5 minutes of 12 rpm. The blend was then transferred to aKilian T-100 rotary tablet press and compressed to a target weight of300 mg and a target thickness of 6.65 mm using 5.500″ B-type 0.3051″Modified Ball Upper Punch and a 4.755″ B-type 0.3051″ Flat Face BevelEdge Lower Punch.

TABLE 30 Quantity Batch Quantity Component: Grade: (mg)/unit: % (grams)Polyethylene Oxide NF 154.50 51.5% 2060.00 Coagulant Grade^(a) SodiumChloride^(b) USP/EP 104.40 34.8% 1392.00 Microcrystalline NF/EP 39.0013.0% 520.00 Cellulose^(c) FD&C Blue No2 Food 0.60  0.2% 8.00 LakeDye^(d) Magnesium Stearatee NF/EP 1.50  0.5% 20.00 300.00 100.0% 4000.00Capsule Shell

2.5 kg of pre-coating solution was prepared by combining 25 grams ofpolysorbate 80 with 2475 grams of acetone and mixing for 10 minutes oruntil dissolved to yield a 1% (w/w) solution.

15 kg of functional coating solution was prepared according to thefollowing steps (see also Table 31): First, the 375 grams of water and61.5 grams of PEG 3350 were added to a suitable vessel and mixed. 14,325grams of acetone were added to the mixture and mixed. 225 grams ofcellulose acetate were added to the mixture and mixed. 13.5 Grams of TECwere added to the mixture and mixed until a uniform solution wasobtained. This procedure creates a 2% solids (w/w) solution.

TABLE 31 Batch % in mg in mg in Quantity Composition of capsule shellscoating cap body (grams) 1. Cellulose Acetate (Type 398-10) 1.50% 73.169.38 225 2. Polyethylene Glycol 3350 0.41% 20.0 18.69 61.5 3. TriethylCitrate (TEC) 0.09% 4.4 4.16 13.5 4. Acetone 95.5% (4655.6) (4416.9)(14,325) 5. Purified water  2.5%  (121.9)  (115.6)   (375) Total Weight100% 97.5 92.5 15,000

1 kg of HDPE capsule molds (either raps or bodies) were coated in aVector LDCS-5 with a 1.5-Liter semi-perforated pan operating at 18 rpmand an airflow of 40 CFM having an exhaust temperature of 40 deg C.After briefly coating the molds with, the 1% w/w pre-coating solution,the functional 2% solids (w/w) coating solution was sprayed at a rate of20 grams/min with atomizing air pressure of 10 psi and a gun-to-beddistance of 3 inches until the wet weight gain reached a level of 12.5%.The capsule molds were then removed from coating pan and dried at 40 Cfor 24 hours. The capsule shells were then removed from the molds andtrimmed.

A single hole (2000 microns) was drilled in the end of the capsulebodies. The hole can be drilled either by mechanical means or via laserablation.

Assembly

The Active Layer is inserted into the half of the capsule shell with thepre-drilled hole. The Sweller Layer is inserted into the same half ofthe capsule shell, flat side first, to be flush against the activelayer. These components are inserted into the other half of the capsuleshell until the capsule is closed. When prepared and combined in thismanner, these components provide the following release in pH 6.8 media,paddles at 50 rpm based on Dissolution test 1 (Table 32).

TABLE 32 Time (hr) % Drug Dissolved 1 1 2.5 4 5 21

80% of tofacitinib is dissolved in about 14 hours in dissolution method1.

Example 12. Hydrophilic Matrix Controlled Release Tablet

The metal surfaces of a 10 L bin were pre-coated by adding the batchquantity (also see Table 33 below), 963 g of Lactose Fast Flo 316 andblending for 2 minute at 12+/−1 RPM. The batch quantity of Tofacitinib,164 g was added to the 10 L bin and folded into the lactose monohydrate.The Tofacitinib container was rinsed with some of the lactosemonohydrate from the 10 L bin. The batch quantity of Hypromellose, 1150g, was added to the 10 L bin. All of the components were blended in thebin for 10 minutes at 12+/−1 RPM.

The blend was passed through a Comil rotary mill equipped with a 0.032″screen and a round edge impeller running at approximately 1400 RPM. Theblend was collected in a second 10 L bin. The bin contents were blendedfor 10 minutes at 12+/−1 RPM.

Intragranular magnesium stearate, 5.75 g, was added to the bin andblended for 3 minutes at 12+/−1 RPM. The lubricated blend was processedthrough a Gerteis roller compactor equipped with knurled rollers, siderims, and an inline oscillating mill containing a pocket rotor and a1-mm rasping plate. The target ribbon solid fraction is 0.7 (0.67-0.73)and granules were collected in the initial 10 L bin.

Extragranular magnesium stearate, 17.25 g, was added to the bin andcontents were blended for 3 minutes at 12+/−1 RPM. Final blend wasaffixed above a Kilian T-100 rotary tablet press. Tablets werecompressed using 13/32″ SRC tooling, to an average target weight of 500mg+/−5% and a target hardness of 15 kP. Tablets were passed through adeduster and a metal detector.

TABLE 33 22 mg Tofacitinib hydrophilic matrix tablet composition; Totaltablet weight 500 mg Ingredient Function % Composition Grams TofacitinibCitrate Active ingredient  7.1% 164.00 Methocel K100LV CR Polymer, gelformer  50% 1150.00 Premium Grade providing controlled release LactoseMonohydrate, Filler 41.9% 963 Fast Flo 316 Magnesium stearate, Lubricant0.25% 5.75 vegetable grade (IG) Magnesium stearate, Lubricant 0.75%17.25 vegetable grade (EG) Total  100% 2300.00

The compressed tablets provide the following release in pH 6.8 media,paddles at 50 rpm based on Dissolution test 1 (Table 34).

TABLE 34 Time (hr) % Drug Dissolved 1 16 2.5 32 5 54

Example 13. 10 mg Immediate Release Tablet

TABLE 35 Composition of the formulation of Example 13 Unit CompositionComponent Name Grade (mg) 1. Tofacitinib Citrate Pharm 16.155 2.Microcrystalline Cellulose Ph.Eur/NF 245.23 3. Lactose MonohydratePh.Eur/NF 122.615 4. Croscarmellose Sodium Ph.Eur/NF 12.000 5. MagnesiumStearate Ph.Eur/NF 1.000 6. Magnesium Stearate Ph.Eur/NF 3.000 TABLETCORE WEIGHT: 400.000 7. Opadry II White (HPMC based) Pharm 12.000 8.Purified Water Ph.Eur/USP (68.000) Total: 412.000 mg

The tablet formulation of Example 13 is manufactured according to thefollowing process. Components 1-4 are combined and processed using ablend-mill-blend procedure. Component 5 is then added to the blendcontents and combined using a blending procedure. This lubricated blendis than dry granulated. Component 6 is then added to the dry granulationand combined using a blending procedure. The lubricated granulation iscompressed into 400 mg weight tablets using a rotary tablet press. Thetablets are then coated using a film coater which sprays a solutioncontaining Components 7 and 8 until 12 mg of coating has been applied tothe tablets.

Example 14. 5 mg Immediate Release Tablet

TABLE 36 Composition of the formulation of Example 14 Unit CompositionComponent Name Grade (mg) 1. Tofacitinib Citrate Pharm 8.078 2.Microcrystalline Cellulose Ph.Eur/NF 314.615 3. Lactose MonohydratePh.Eur/NF 157.307 4. Croscarmellose Sodium Ph.Eur/NF 15.000 5. MagnesiumStearate Ph.Eur/NF 2.500 6. Magnesium Stearate Ph.Eur/NF 2.500 TABLETCORE WEIGHT: 500.000 7. Opadry II White (HPMC based) Pharm 20.000 8.Purified Water Ph.Eur/USP (113.333) Total: 520.000 mg

The tablet is manufactured according to the following process.Components 1-4 are combined and processed using a blend-mill-blendprocedure. Component 5 is then added to the blend contents and combinedusing a blending procedure. This lubricated blend is than drygranulated. Component 6 is then added to the dry granulation andcombined using a blending procedure. The lubricated granulation iscompressed into 500 mg weight tablets using a rotary tablet press. Thetablets are then coated using a film coater which sprays a solutioncontaining Components 7 and 8 until 20 mg of coating has been applied tothe tablets.

Example 15. Study A

The relative bioavailability of a single dose of 2 different oralsustained release formulations of 20 mg tofacitinib relative to a singledose of 10 mg tofacitinib immediate release (IR) tablets were performedand the following endpoints for tofacitinib were determined: C_(max),T_(max), AUC_(inf), AUC_(last). An additional endpoint was determinedfor the relative bioavailability (% RBA) of tofacitinib for eachsustained release formulations relative to the IR formulation.

The study was a randomized, open-label, single dose, 3-period,3-treatment, 6-sequence crossover study in 12 healthy male subjects (SeeTable 37). Subjects received two different sustained releaseformulations of tofacitinib and the immediate release tablet formulationwith a washout period of 3 days between doses. The sustained releaseformulations were given as a 20 mg single dose and the immediate releaseformulation was given as two 5 mg tablets in a single dose.

TABLE 37 Period Sequence 1 2 3 ABC (n = 2) A B C BCA (n = 2) B C A CAB(n = 2) C A B ACB (n = 2) D E C BAC (n = 2) E A D CBA (n = 2) A E B A:Immediate Release Tablet , 10 mg; B: Example 10 bilayer osmotic capsule,20 mg; C: Example 11 bilayer osmotic capsule, 20 mg;Subjects were fasted overnight for at least 8 hours prior toadministration of the study drug. On the morning of Day 1 of eachperiod, all subjects received a single oral dose of study drug with 240mL of water. Subjects were allowed a standardized lunch 4 hours afterdose administration.

Dosage Forms Administered:

Tofacitinib 10 mg Immediate Release Control Tablet (reference): preparedin Example 13.

Tofacitinib 20 mg bilayer osmotic capsule: prepared in Example 10.

Tofacitinib 20 mg bilayer osmotic capsule: prepared in Example 11.

During all study periods, blood samples to provide plasma forpharmacokinetic analysis was collected at periodic time points. PKsamples were analyzed using standard validated analytical methods. Dosenormalized natural log transformed AUC_(inf), AUC_(last) and C_(max) areanalyzed for tofacitinib using a mixed effect model with sequence,period and treatment as fixed effects and subject within sequence as arandom effect. Estimates of the adjusted mean differences(Test−Reference) and corresponding 90% confidence intervals wereobtained from the model. The adjusted mean differences and 90%confidence intervals for the differences was exponentiated to provideestimates of the ratio of adjusted geometric means (Test/Reference) and90% confidence intervals for the ratios. The immediate release controltablet formulation was the Reference treatment and the sustained releaseformulations were the Test treatments.

The relative bioavailability of tofacitinib was estimated as the ratioof dose-normalized adjusted geometric means for Test and Reference forAUC_(inf).

The PK parameters AUC_(inf), AUC_(last), C_(max), T_(max), and t_(1/2)were summarized descriptively by treatment and analyte (whenapplicable). For AUC_(inf) and C_(max), individual subject parameterswere plotted by treatment for each analyte separately (when applicable).Concentrations were listed and summarized descriptively by PK samplingtime, treatment and analyte (when applicable). Individual subject, meanand median profiles of the concentration-time data were plotted bytreatment and analyte (when applicable). For summary statistics, andmean and median plots by sampling time, the nominal PK sampling timewere used, for individual subject plots by time, the actual PK samplingtime were used.

Predicted steady-state values were obtained via the superposition methodusing the software package WinNonLin (Pharsight Corp), Superposition wasused on each individual's pharmacokinetic profile to generate thesteady-state pharmacokinetic profile of each individual. The definitionsand method of determination of PK parameters are given in Table 38. Theresults of the study are shown in Table 39.

TABLE 38 Parameter Definition Method of Determination AUC_(last) Areaunder the plasma Log-linear trapezoidal concentration-time profilemethod from time zero to the time of the last quantifiable concentration(C_(last)) AUC_(inf) Area under the plasma AUC_(last) +(C_(last)*/k_(el)), where concentration-time profile C_(last)* is thepredicted from time zero extrapolated plasma concentration at toinfinite time the last quantifiable time point estimated from thelog-linear regression analysis. AUC_(inf,dn) Area under the plasmaAUC_(inf)/dose concentration-time profile from time zero extrapolated toinfinite time divided by the dose administered C_(max) Maximum plasmaObserved directly from concentration data C_(max,dn) Maximum plasmadivided by C_(max)/dose the dose administered concentration T_(max) Timefor C_(max) Observed directly from data as time of first occurrencet_(1/2) Terminal elimination half-life Loge(2)/k_(el), where k_(el) isthe terminal phase rate constant calculated by a linear regression ofthe log-linear concentration- time curve. Only those data points judgedto describe the terminal log- linear decline will be used in theregression. C_(min,ss) Minimum plasma Observed from steady-concentration during the state pharmacokinetic course of one, 24 hourprofile data, which is interval once steady-state calculated from singlehas been achieved dose data using the superposition method C_(min,dn,ss)Minimum plasma C_(min,ss)/dose concentration during the course of one,24 hour interval once steady-state has been achieved C_(max,ss) Maximumplasma Observed from steady- concentration during the statepharmacokinetic course of one, 24 hour profile data, which is intervalonce steady-state calculated from single has been achieved dose datausing the superposition method C_(max,ss)/C_(min,ss) Ratio of maximumand C_(max,ss)/C_(min,ss) minimum plasma concentrations during thecourse of one, 24 hour interval once steady-state has been achieved Timeabove Period of time during the Observed from steady- 17 ng/ml course ofone, 24 hour state pharmacokinetic interval of steady-state profiledata, which is dosing that the plasma calculated from singleconcentration is 17 ng/ml dose data using the superposition method Drugholiday Period of time during the Observed from steady- (Time belowcourse of one, 24 hour state pharmacokinetic 17 ng/ml) interval ofsteady-state profile data, which is dosing that the plasma calculatedfrom single concentration is below 17 dose data using the ng/mlsuperposition method

TABLE 39 20 mg 20 mg Example 10 Example 11 Single 10 mg IR OsmoticOsmotic Dose PK Tablet Capsule Capsule Parameters (Reference) (Test)(Test) C_(max) (ng/ml) 121.5 (30%) 41.8 (24%) 18.2 (16%) C_(max,dn)(ng/ml/mg) 12.1 (30%) 2.1 (24%) 0.9 (16%) AUC_(inf) (ng*hr/ml) 339.5(17%) 543.6 (23%) 390.2 (38%) AUC_(inf,dn) ng*hr/ml/mg) 34.0 (17%) 27.2(23%) 18.8 (38%) t½ (hr) 3.35 (13%) 5.84 (23%) 6.07 (53%) T_(max) (hr)0.5 (0.25-2) 5 (4-10) 13 (4-24) Dose Normalized 100% 17% (14-20%) 7.5%(6-9%) C_(max) Ratio (%) Dose Normalized 100% 80% (65-99%) 55% (45-69%)RBA (%) The above values are reported as Geometric mean (% coefficientof variation (CV)) for all except: median (range) for Tmax; arithmeticmean (% CV) for t½. The above ratios are presented as geometric meanratio (90% Confidence Intervals). 20 mg 25 mg 20 mg 33 mg Example 10Example 10 Example 11 Example 11 Predicted 10 mg Osmotic Osmotic OsmoticOsmotic Steady-State IR BID Capsule Capsule Capsule Capsule PK(Reference) QD (Test) QD* (Test) QD (Test) QD* (Test) C_(max,ss) (ng/ml)125.4 (30%) 46.0 (24%) 57.5 (24%) 23.7 (30%) 39.1 (30%) C_(min,ss)(ng/ml) 3.7 (39%) 6.1 (37%) 7.7 (37%) 9.9 (76%) 16.3 (76%) C_(min,dn,ss)0.19 (39%) 0.31 (37%) 0.31 (37%) 0.50 (76%) 0.50 (76%) (ng/ml/mg)C_(min,ss) Ratio (%) 100% 166% 207% 267% 441% (128-215%) (160-268%)(123-581%) (203-958%) C_(max,ss)/C_(min,ss) 34 7.5 7.5 2.4 2.4 Timeabove 12.6 13.1 15.1 16.9 18.6 17 ng/ml (hrs) (2 × 6.3 hrs) Drug holiday11.4 10.9 8.9 7.1 5.4 (Time below 17 ng/ml) (hrs)_ The above parametersare presented as geometric mean (% CV). The above ratios are presentedas geometric mean ratio (90% Confidence Intervals). *necessary doseadjustment to achieve 100% RBA with those durations of modified release

The results of this study show that sustained release dosage forms whichrequire 6 hours or longer to release and dissolve 80% of tofacitinib donot meet the desired pharmacokinetic attributes for tofacitinibsustained release dosage forms. Specifically, a sustained release dosageform which requires 6 hours or longer to release and dissolve 80% oftofacitinib, and has the required amount of tofacitinib to provide anequivalent AUC value to the immediate release dosage form, provides atime above 17 ng/ml (the JAK 1/3 receptor IC₅₀ value) which is greaterthan the time above 17 ng/ml for the immediate release dosage form.Further, a sustained release dosage form which requires 14 hours torelease and dissolve 80% of tofacitinib has a higher dose-normalizedCmin,ss, a lower dose-normalized AUC, and a low relative bioavailabilityto the immediate release dosage form, which requires an increase in thedrug loading of tofacitinib to have equivalent AUC to the immediaterelease dosage form. These results support the requirement of asustained release dosage form of tofacitinib requiring less than 6 hoursto release and dissolve 80% of tofacitinib.

Example 16. Study B

The relative bioavailability of 3 different oral sustained releaseformulations of 22 mg tofacitinib relative to a single dose of 10 mgtofacitinib immediate release (IR) tablets were performed and thefollowing endpoints for tofacitinib were determined: C_(max), T_(max),AUC_(inf), AUC_(last). An additional endpoint was determined for therelative bioavailability (% RBA) of tofacitinib for each sustainedrelease formulations relative to the IR formulation.

The study was a randomized, open-label, single dose, 4-period,6-treatment, 6-sequence partial crossover study in 30 healthy malesubjects (See 40). In the first period, subjects received one of twodifferent sustained release formulations of tofacitinib in the fedstate. In the second and third periods, subjects received 2 of threesustained release formulations. In the fourth period, subjects receivedthe immediate release tablet formulation. A washout period of 3 days wasused between doses. The three sustained release formulations are givenas a 22 mg single dose and the immediate release formulation is given astwo 5 mg tablets in a single dose.

TABLE 40 Period 1 2 3 4 Sequence (fed) (fasted) fasted) (fasted) 1 (n =5) A C D F 2 (n = 5) A C E F 3 (n = 5) B D E F 4 (n = 5) B D C F 5 (n =5) A E C F 6 (n = 5) B E D F A: 4-hr Extrudable Core System Tablet, 22mg, fed state; B: Example 4 Matrix Tablet, 22 mg, fed state; C: 4-hrExtrudable Core System Tablet, 22 mg, fasted state; D: Example 4 MatrixTablet, 22 mg, fasted state; E: Example 12 Matrix Tablet, 22 mg, fastedstate; F: Immediate Release Tablet, 2 × 5 mg, fasted state;In Period 1, after an overnight fast of at least 8 hours, subjects wereadministered the standard high-fat FDA breakfast 30 minutes prior toadministration of the study drug. Breakfast was consumed within 30minutes or less. Subjects received either Treatment A or Treatment Badministrations 30 minutes (+/−5 minutes) after the initiation ofbreakfast. No additional food was allowed for at least 4 hourspost-dose. Water was withheld for 1 hour pre-dose and 1 hour after thestudy drug administration. Dosing in Periods 1, 2, and 3 was followed bya minimum washout of 72 hours. The next period of the study (Periods 2,3, and 4) started immediately following completion of the 72-hour PKsample procedures on Day 4 of the preceding period (Periods 1, 2, and 3respectively). In Periods 2, 3, and 4, study drug was administered afteran overnight fast of at least 8 hours. Food was only allowed after 4hours post-dose. Water was withheld for 1 hour pre-dose and 1 hour afterstudy drug administration.

Dosage Forms Administered:

Tofacitinib 5 mg Immediate Release Tablet (reference): prepared inExample 14 above.

Tofacitinib 22 mg Extrudable Core System Tablet: prepared in Example 1above.

Tofacitinib 22 mg Matrix Tablets: prepared in Example 4 and 12 above.

During all study periods, blood samples to provide plasma forpharmacokinetic analysis was collected at periodic time points. Thestudy results are provided in Table 41. PK samples were analyzed usingstandard validated analytical methods. Dose normalized natural logtransformed AUCinf, AUClast and Cmax was analyzed for tofacitinib usinga mixed effect model with sequence, period and treatment as fixedeffects and subject within sequence as a random effect. Estimates of theadjusted mean differences (Test−Reference) and corresponding 90%confidence intervals were obtained from the model. The adjusted meandifferences and 90% confidence intervals for the differences wasexponentiated to provide estimates of the ratio of adjusted geometricmeans (Test/Reference) and 90% confidence intervals for the ratios. Theimmediate release control tablet formulation was the Reference treatmentand the sustained release formulations were the Test treatments.

The relative bioavailability of tofacitinib was estimated as the ratioof dose-normalized adjusted geometric means for Test and Reference forAUC_(inf).

The PK parameters AUC_(inf), AUC_(last), C_(max), T_(max), and t_(1/2)are summarized descriptively by treatment and analyte (when applicable).For AUC_(inf) and C_(max), individual subject parameters were plotted bytreatment for each analyte separately (when applicable). Concentrationsare listed and summarized descriptively by PK sampling time, treatmentand analyte (when applicable). Individual subject, mean and medianprofiles of the concentration-time data were plotted by treatment andanalyte (when applicable). For summary statistics, and mean and medianplots by sampling time, the nominal PK sampling time were used, forindividual subject plots by time, the actual PK sampling time were used.

Predicted steady-state values were obtained via the superposition methodusing the software package WinNonLin (Pharsight Corp). Superposition wasused on each individual's pharmacokinetic profile to generate thesteady-state pharmacokinetic profile of each individual.

TABLE 41 Single dose, 10 mg IR 22 mg 22 mg Matrix 22 mg MatrixBioavailability Tablet ECS (Example 4) (Example 12) Evaluation(Reference) (Test) (Test) (Test) C_(max) (ng/ml) 108 (28%) 101 (28%) 89(29%) 59 (29%) C_(max,dn) (ng/ml/ mg) 10.8 (28%) 4.6 (28%) 4.0 (29%) 2.7(29%) AUC_(inf) (ng*hr/ml) 367 (24%) 757 (23%) 781 (27%) 702 (23%)AUC_(inf,dn) 36.7 (24%) 34.4 (23%) 35.5 (27%) 31.9 (23%) (ng*hr/ml/mg)T_(max) (hr) 0.5 (0.5-4.0) 4.0 (2.0-6.0) 2.5 (1.0-6.0) 3.0 (2.0-4.0) t½(hr) 3.7 (13%) 5.6 (60%) 5.3 (51%) 6.0 (46%) C_(max) Ratio (%) 100% 92%(82%-104%) 84% (75%-94%) 56% (50%-62%) Dose Normalized 100% 91%(87%-96%) 97% (92%-101%) 89% (85%-94%) RBA % The above values arereported as Geometric mean (% CV) for all except: median (range) forTmax; arithmetic mean (% CV) for t½ . The above ratios are presented asgeometric mean ratio (90% Confidence Intervals). Single Dose, FoodEffect 22 mg ECS 22 mg Matrix (Example 4) Fasted Fed Fasted FedEvaluation (Reference) (Test) (Reference) (Test) C_(max) (ng/ml) 101(28%) 113 (20%) 89 (29%) 136 (25%) AUC_(inf) (ng*hr/ml) 757 (23%) 732(21%) 781 (27%) 823 (24%) T_(max) (hr) 4.0 (2.0-6.0) 4.0 (3.0-6.0) 2.5(1.0-6.0) 3.0 (2.0-6.0) t½ (hr) 5.6 (60%) 4.9 (31%) 5.3 (51%) 4.8 (56%)C_(max) Ratio (%) 100% 113% (100-128%) 100% 153% (135-174%) RBA ( %)100% 100% (95-106%) 100% 105% (99-110%) The above values are reported asGeometric mean (% CV) for all except: median (range) for Tmax;arithmetic mean (% CV) for t12. The above ratios are presented asgeometric mean ratio (90% Confidence Intervals). 22 mg Matrix 22 mgMatrix 10 mg 22 mg QD QD IR BID ECS QD (Example 4) (Example 12)Predicted Fasted Fasted Fasted Fasted Steady-State PK (Reference) (Test)(Test) (Test) C_(max,ss) (ng/ml) 112.7 (30%) 104.5 (30%) 92.6 (32%) 66.2(27%) C_(min,ss) (ng/ml) 5.0 (66%) 3.80 (92%) 3.31 (89%) 7.36 (60%)C_(min,dn,ss) (ng/ml/ mg) 0.25 (66%) 0.17 (92%) 0.15 (89%) 0.33 (60%)C_(min,ss) Ratio (%) 100% 74% (59-92%) 64% (51-81%) 159% (134-190%)C_(max,ss)/C_(min,ss) 23 28 28 9 Time above 13.4 13.2 14.1 17.6 17 ng/ml(hrs) (2 × 6.7 hrs) Drug holiday 10.6 10.8 9.9 6.4 (time below 17 ng/ml)(hrs) The above parameters are presented as geometric mean (% CV). Theabove ratios are presented as geometric mean ratio (90% ConfidenceIntervals).

Sustained-release dosage forms containing 22 mg of tofacitinib whichrelease and dissolve 80% of tofacitinib in 4-5 hours providedose-proportional pharmacokinetic performance and meet the desiredpharmacokinetic claims when dosed in the fasted state. Sustained-releasedosage forms containing 22 mg of tofacitinib which release and dissolve80% of tofacitinib by osmotic pressure in 4 hours provide similarpharmacokinetic performance when administered in both the fed and fastedstates. Sustained-release dosage forms containing 22 mg of tofacitinibwhich release and dissolve 80% of tofacitinib by matrix diffusion anderosion in 5 hours do not provide similar Cmax performance whenadministered in both the fed and fasted states.

Example 17. Study C

The relative bioavailability of a single dose of an oral sustainedrelease formulation of 11 mg tofacitinib relative to a single dose of 22mg tofacitinib sustained release tablets was performed and the followingendpoints for tofacitinib are determined: C_(max), T_(max), AUC_(inf),AUC_(last). An additional endpoint was determined for the dosenormalized relative bioavailability (% RBA) of tofacitinib for the 11 mgsustained release formulations relative to the 22 mg sustained releaseformulation.

The study was a randomize open-label, single dose, 2-period,2-treatment, 2-sequence crossover study in 20 healthy male subjects (SeeTable 42), Subjects received two different sustained releaseformulations of tofacitinib with a washout period of 3 days betweendoses. The sustained release formulations were given as an 11 or 22 mgsingle dose.

TABLE 42 Period Sequence 1 2 AB (n = 10) A B BA (n = 10) B A A:Extrudable CoreSystem Tablet , 11 mg; prepared in Example 1 above. B:Extrudable CoreSystem Tablet , 22 mg; prepared in Example 1 above.Subjects were fasted overnight for at least 8 hours prior toadministration of the study drug. On the morning of Day 1 of eachperiod, all subjects received a single oral dose of study drug with 240mL of water. Subjects were allowed a standardized lunch 4 hours afterdose administration.

Dosage Forms Administered:

Tofacitinib 22 mg Sustained Release dosage forms: prepared in Example 1above.

Tofacitinib 11 mg Sustained Release dosage forms: prepared in Example 1above.

During all study periods, blood samples to provide plasma forpharmacokinetic analysis was collected at periodic time points. Thestudy results are provided in Table 43. PK samples were analyzed usingstandard validated analytical methods. Dose normalized natural logtransformed AUCinf, AUClast and Cmax were analyzed for tofacitinib usinga mixed effect model with sequence, period and treatment as fixedeffects and subject within sequence as a random effect. Estimates of theadjusted mean differences (Test−Reference) and corresponding 90%confidence intervals were obtained from the model. The adjusted meandifferences and 90% confidence intervals for the differences wasexponentiated to provide estimates of the ratio of adjusted geometricmeans (Test/Reference) and 90% confidence intervals for the ratios. The22 mg sustained release formulation was the Reference treatment and the11 mg sustained release formulation was the Test treatments.

The relative bioavailability of tofacitinib was estimated as the ratioof dose-normalized adjusted geometric means for Test and Reference forAUC_(inf).

The PK parameters AUC_(inf), AUC_(last), C_(max), T_(max), and t_(1/2)were summarized descriptively by treatment and analyte (whenapplicable). For AUC_(inf) and C_(max), individual subject parametersare plotted by treatment for each analyte separately (when applicable).Concentrations were listed and summarized descriptively by PK samplingtime, treatment and analyte (when applicable). Individual subject, meanand median profiles of the concentration-time data were plotted bytreatment and analyte (when applicable). For summary statistics, andmean and median plots by sampling time, the nominal PK sampling timewere used, for individual subject plots by time, the actual PK samplingtime were used.

Predicted steady-state values were obtained via the superposition methodusing the software package WinNonLin (Pharsight Corp). Superposition wasused on each individual's pharmacokinetic profile to generate thesteady-state pharmacokinetic profile of each individual.

TABLE 42 11 mg 22 mg Single Dose PK Parameters (Test) (Reference)C_(max) (ng/ml) 42.2 (32%) 84.4 (22%) C_(max,dn) (ng/ml/ mg) 3.84 (32%)3.84 (22%) AUC_(inf) (ng*hr/ml) 315.6 (21%) 645.8 (23%) AUC_(inf,dn)(ng*hr/ml/mg) 28.7 (21%) 29.4 (23%) T_(max) (hr) 3.0 (2.0-4.0) 3.0(2.0-4.0) t½ (hr) 6.25 (36%) 7.3 (46%) C_(max,dn) Ratio (%) 100%(91-110%) 100% AUC_(inf,dn) Ratio (%) 98% (95-101%) 100% The abovevalues are reported as Geometric mean (% CV) for all except: median(range) for Tmax; arithmetic mean (% CV) for t12. The above ratios arepresented as geometric mean ratio (90% Confidence Intervals). 11 mg QD22 mg QD Predicted Steady-State PK (Test) (Reference) C_(max,ss) (ng/ml)43.6 (35%) 87.6 (25%) C_(min,ss) (ng/ml) 1.7 (53%) 3.5 (75%)C_(min,dn,ss) (ng/ml/ mg) 0.15 (53%) 0.16 (75%) C_(min,dn,ss) Ratio (%)95% (72-125%) 100% C_(max,ss)/C_(min,ss) 26 25 Time above 17 ng/ml (hrs)6.6 11.1 Drug holiday (Time below 17 ng/ml) (hrs) 17.4 12.9 The aboveparameters are presented as geometric mean (% CV). The above ratios arepresented as geometric mean ratio (90% Confidence Intervals).

Sustained-release dosage forms containing 11 mg and 22 mg of tofacitinibwhich release and dissolve tofacitinib according to the claims (based ondissolution test 1) provide dose-proportional pharmacokineticperformance and meet the desired pharmacokinetic claims.

Example 18. Study D

The relative bioavailability of 11 mg tofacitinib sustained releasetablets relative to a single dose of two, 5 mg tofacitinib immediaterelease (IR) tablets were performed and the following endpoints fortofacitinib were determined: C_(max), T_(max), AUC_(inf), AUC_(last). Anadditional endpoint was determined for the relative bioavailability (%RBA) of tofacitinib for each sustained release formulations relative tothe IR formulation.

The study was a randomized, opera-label, single dose, 2-period,2-treatment, 2-sequence crossover study in 26 healthy subjects (SeeTable 44), Subjects received either the 11 mg sustained releaseformulations of tofacitinib citrate or two, 5 mg immediate releaseformulation of tofacitinib citrate with a washout period of 3 daysbetween doses.

TABLE 44 Period Sequence 1 2 AB (n = 13) A B BA (n = 13) B A

A: Extrudable Core System Tablet, 11 mg; Prepared as Follows:

TABLE 45 Composition 300 kg # Material Function (%) Batch 1 TofacitinibCitrate Active 8.885 26.656 2 Sorbitol Osmagen 76.115 228.344 3Hydroxyethylcellulose Viscosifying 8.000 24.000 Agent 4 CopovidoneBinder 6.000 18.000 5 Magnesium Stearate Lubricant 1.000 3.000 CoreTablet Weight — 100% 300.000 kg

One-half of the batch quantity of sorbitol, 114.172 kilograms, was addedto an 800 L bin. The batch quantity of Copovidone, 18.000 kilograms, wasthen added to the 800 L bin. The batch quantity of Tofacitinib, 26.656kilograms, was then added to the 800 L bin. The batch quantity ofHydroxycellulose, 24.000 kilograms, was then added to the 800 L bin. Theremaining one-half of the batch quantity of sorbitol, 114.172 grams wasadded to the 800 L bin. All materials were added via a vacuum transfersystem and passed through a Comil rotary mill equipped with a 0.032″screen and a round edge impeller running at approximately 1400 RPM. Allof the components are blended in the bin for 20 minutes at 12+/−1 RPM.

The blend was passed through a Comil rotary mill equipped with a 0.032″screen and a round edge impeller running at approximately 1400 RPM. Theblend was collected in a second 800 L bin. The bin contents were blendedfor 20 minutes at 12+/−1 RPM.

Magnesium stearate, 3.000 kilograms, was passed through an 850-micronmesh screen and was added to the bin and contents are blended for 5minutes at 12+/−1 RPM. Tablets were compressed using 0.2080″×0.4160″modified oval tooling on a Manesty Mark IV rotary tablet press, to anaverage target weight of 200 mg+/−5%, average target thickness of 4.17mm+/−0.05 mm, and a target hardness of 11 kp. Tablets were passedthrough a deduster and a metal detector.

TABLE 46 coat Batch Composition of coated % in mg/ w/w Quantity 200 mgWtablet coating tablet (%) (kilograms) 1. Tofacitinib Citrate Tablet Core— 200 — — 2. Cellulose Acetate  1.8% 8.4 4.2 13.5 (Type 398-10) 3.Hydroxypropyl  1.2% 5.6 2.8 9.0 (Cellulose Klucel EF) 4. Methanol 19.6%(91.5)  — 147.0 5. Acetone 77.4% (361.2) — 580.5 Total Weight 100% 214.07.0 750.0

The 750-kilogram coating solution was prepared according to thefollowing steps. First, the entire 147.0 kilograms of methanol and 580.5grams of acetone were added to a 250-gallon vessel. 13.5 kilograms ofcellulose acetate were added to the mixture. 9.0 kilogram ofhydroxypropyl cellulose were added to the mixture. The contents of thecontainer were mixed for 1 hour. This procedure created a 3% solids(w/w) solution.

250 kilograms of the 200 mg weight oval tablets were coated in a VectorHC-130 operating at 8 rpm and an airflow of 1500 CFM having an exhausttemperature of 28 deg C. The 3% solids (w/w) solution was applied untilthe wet weight gain reached a level of 7%. The tablets were then removedfrom the coating pan and dried at 45 C for 24 hours.

A single hole (600 micron) was drilled in the end of the band of theoval tablet. The hole can be drilled either by mechanical means or vialaser ablation. A coating of 7% provided the following release in pH 6.8media, paddles at 50 rpm based on Dissolution test 1 (Table 47):

TABLE 47 Time 11 mg Tablet (hr) % Drug Dissolved 1 8 2.5 49 6 89

B: Tofacitinib 2×5 mg Immediate Release Tablet (Reference) Prepared asFollows:

TABLE 48 Composition of the 5 mg Immediate Release Tablet UnitComposition Component Name Grade (mg) 1. Tofacitinib Citrate Pharm 8.0782. Microcrystalline Cellulose Ph.Eur/NF/JP 122.615 3. LactoseMonohydrate Ph.Eur/NF/JP 61.307 4. Croscarmellose Sodium Ph.Eur/NF/JP6.000 5. Magnesium Stearate Ph.Eur/NF/JP 0.500 6. Magnesium StearatePh.Eur/NF/JP 1.500 TABLET CORE WEIGHT: 200.000 7. Opadry II White (HPMCbased) Pharm 6.000 8. Purified Water Ph.Eur/USP/JP (34.000) Total:206.000 mg

The tablet is manufactured according to the following process.Components 1-4 are combined and processed using a blend-mill-blendprocedure. Component 5 is then added to the blend contents and combinedusing a blending procedure. This lubricated blend is than drygranulated. Component 6 is then added to the dry granulation andcombined using a blending procedure. The lubricated granulation iscompressed into 200 mg weight tablets using a rotary tablet press. Thetablets are then coated using a film coater which sprays a solutioncontaining Components 7 and 8 until 6 mg of coating has been applied tothe tablets.

Subjects were fasted overnight for at least 8 hours prior toadministration of the study drug. On the morning of Day 1 of eachperiod, all subjects received a single oral dose of study drug with 240mL of water. Subjects were allowed a standardized lunch 4 hours afterdose administration.

Dosage Forms Administered:

Tofacitinib 5 mg Immediate Release Tablet (reference): prepared asdescribe above.

Tofacitinib 11 mg Sustained Release dosage forms: prepared as describedabove.

During all study periods, blood samples to provide plasma forpharmacokinetic analysis was collected at periodic time points. Thestudy results are provided in Table 49. PK samples were analyzed usingstandard validated analytical methods. Dose normalized natural logtransformed AUC_(inf), AUC_(last) and C_(max) were analyzed fortofacitinib using a mixed effect model with sequence, period andtreatment as fixed effects and subject within sequence as a randomeffect. Estimates of the adjusted mean differences (Test−Reference) andcorresponding 90% confidence intervals were obtained from the model. Theadjusted mean differences and 90% confidence intervals for thedifferences was exponentiated to provide estimates of the ratio ofadjusted geometric means (Test/Reference) and 90% confidence intervalsfor the ratios. The 2×5 mg immediate release formulation was theReference treatment and the 11 mg sustained release formulation was theTest treatment.

The relative bioavailability of tofacitinib was estimated as the ratioof geometric means for Test and Reference for AUC_(inf).

The PK parameters AUC_(inf), AUC_(last), C_(max), T_(max), and t_(1/2)were summarized descriptively by treatment and analyte (whenapplicable). For AUC_(inf) and C_(max), individual subject parametersare plotted by treatment for each analyte separately (when applicable).Concentrations were listed and summarized descriptively by PK samplingtime, treatment and analyte (when applicable). Individual subject, meanand median profiles of the concentration-time data were plotted bytreatment and analyte (when applicable). For summary statistics, andmean and median plots by sampling time, the nominal PK sampling timewere used, for individual subject plots by time, the actual PK samplingtime were used.

Predicted steady-state values were obtained via the superposition methodusing the software package WinNonLin (Pharsight Corp). Superposition wasused on each individual's pharmacokinetic profile to generate thesteady-state pharmacokinetic profile of each individual.

TABLE 49 2 × 5 mg 11 mg modified immediate Single Dose PK releaserelease Parameters (Test) (Reference) C_(max) (ng/ml) 40.8 (29%) 88.2(29%) C_(max,dn) (ng/ml/ mg) 3.70 (29%) 8.82 (29%) AUC_(inf) (ng*hr/ml)297.5 (23%) 286.3 (20%) AUC_(inf,dn) (ng*hr/ml/ mg) 27.0 (23%) 28.6(20%) T_(max) (hr) 3.54 (3.00-6.00) 0.50 (0.50-2.00) t½ (hr) 5.705 (41%)3.413 (18%) C_(max(adj)) Ratio (%) 92% (85-100%) 100% AUC_(inf) Ratio(%) 104% (100%-107%) 100% The above values are reported as Geometricmean (% CV) for all except: median (range) for Tmax; arithmetic mean (%CV) for t½ . The above ratios are presented as geometric mean ratio (90%Confidence Intervals). 2 × 5 mg 11 mg modified immediate Predictedrelease QD release BID Steady-State PK (Test) (Reference) C_(max,ss)(ng/ml) 41.6 (31%) 45.0 (28%) C_(min,ss) (ng/ml) 1.3 (60%) 1.5 (53%)C_(min,dn,ss) (ng/ml/ mg) 0.12 (60%) 0.15 (53%) C_(min,dn,ss) Ratio (%)88% (73%-106%) 100% C_(max,ss)/C_(min,ss) 32 30 Time above 17 ng/ml(hrs) 6.3 5.6 Drug holiday (Time below 17 ng/ml) (hrs) 17.7 18.4 Theabove parameters are presented as geometric mean (% CV). The aboveratios are presented as geometric mean ratio (90% Confidence Intervals).

Sustained-release dosage forms containing 11 mg of tofacitinib whichrelease and dissolve 80% of tofacitinib in 4-5 hours providepharmacokinetic performance similar to immediate release dosage formscontaining 10 mg of tofacitinib and meet the desired pharmacokineticclaims when dosed in the fasted state.

We claim:
 1. A once daily pharmaceutical dosage form comprising a corecomprising 11 mg of tofacitinib, or an equivalent amount of tofacitinibin the form of a pharmaceutically acceptable salt thereof, and anosmagen, and a semi-permeable membrane coating surrounding the corewherein said coating comprises a water-insoluble polymer, wherein saiddosage form is a sustained release dosage form, and when added to a testmedium comprising 900 ml of 0.05M pH 6.8 potassium phosphate buffer at37° C. in a standard USP rotating paddle apparatus and the paddles arerotated at 50 rpm, dissolves not more than 30% of the tofacitinib, orpharmaceutically acceptable salt thereof, in 1 hour, and not less than35% and not more than 75% of the tofacitinib, or pharmaceuticallyacceptable salt thereof, in 2.5 hours and not less than 75% of thetofacitinib, or pharmaceutically acceptable salt thereof, in 5 hours andwherein said dosage form delivers the tofacitinib, or pharmaceuticallyacceptable salt thereof, to a subject primarily by osmotic pressure andwherein the water-insoluble polymer is a cellulose derivative thatsustains release of the tofacitinib, or pharmaceutically acceptable saltthereof.
 2. A once daily pharmaceutical dosage form comprising a corecomprising 11 mg of tofacitinib, or an equivalent amount of tofacitinibin the form of a pharmaceutically acceptable salt thereof, and anosmagen, and a semi-permeable membrane coating surrounding the corewherein said coating comprises a water-insoluble polymer, wherein thedosage form is a sustained release dosage form and when administeredorally to a subject provides an AUC in the range of 80% to 125% of theAUC of 5 mg of tofacitinib or an equivalent amount of tofacitinib in theform of a pharmaceutically acceptable salt thereof administered as animmediate release formulation BID and provides a ratio of geometric meanplasma Cmax to Cmin from about 10 to about 100 and wherein the dosageform delivers the tofacitinib, or pharmaceutically acceptable saltthereof, to the subject primarily by osmotic pressure and wherein thewater-insoluble polymer is a cellulose derivative that sustains releaseof the tofacitinib or pharmaceutically acceptable sat thereof.
 3. Thepharmaceutical dosage form of claim 2, wherein the AUC range is 90% to110% and the geometric mean plasma concentration Cmax to Cmin from about20 to about
 40. 4. The pharmaceutical dosage form of claim 3, whereinthe geometric mean plasma concentration Cmax to Cmin from about 20 toabout
 30. 5. The pharmaceutical dosage form of claim 2, wherein when thedosage form is administered orally to the subject provides a mean plasmaCmax in the range of 70% to 125% of the mean plasma Cmax of tofacitinibadministered as the immediate release formulation BID at steady state.6. The pharmaceutical dosage form of claim 2, wherein when the dosageform is administered orally to the subject provides a drug holiday inthe range of 80% to 110% of the drug holiday of tofacitinib administeredas the immediate release formulation BID over a 24 hour period.
 7. Thepharmaceutical dosage form of claim 2, having a drug holiday from about15 to about 18 hours over the 24 hour period.
 8. A once dailypharmaceutical dosage form comprising a core comprising 11 mg oftofacitinib, or an equivalent amount of tofacitinib in the form of apharmaceutically acceptable salt thereof, and an osmagen, and asemi-permeable membrane coating surrounding the core wherein saidcoating comprises a water-insoluble polymer, wherein said dosage form isa sustained release dosage form, and when administered to a subject hasa mean area under the plasma concentration versus time curve followingadministration from about 17 ng-hr/mL per mg of tofacitinib dosed toabout 42 ng-hr/mL per mg of tofacitinib dosed and a ratio of geometricmean plasma Cmax to Cmin from about 10 to about 100 and wherein saiddosage form delivers the tofacitinib, or pharmaceutically acceptablesalt thereof, to the subject primarily by osmotic pressure and whereinthe water-insoluble polymer is a cellulose derivative that sustainsrelease of the tofacitinib or pharmaceutically acceptable salt thereof.9. The pharmaceutical dosage form of claim 8, wherein the ratio ofgeometric mean plasma Cmax to Cmin from about 20 to about
 40. 10. Thepharmaceutical dosage form of claim 9, wherein the ratio of geometricmean plasma Cmax to Cmin from about 20 to about
 30. 11. Thepharmaceutical dosage form of claim 8, wherein the subject has a single,continuous time above about 17 ng/ml from about 6 to about 15 hours anda single, continuous time below about 17 ng/ml from about 9 to about 18hours over a dosing 24 hours interval.
 12. The pharmaceutical dosageform of claim 11, wherein the subject has a single, continuous timeabove about 17 ng/ml from about 6 to about 9 hours.
 13. Thepharmaceutical dosage form of claim 11, wherein the subject has asingle, continuous time below about 17 ng/ml from about 15 to about 18hours.
 14. The pharmaceutical dosage form of claim 11, wherein thesubject has a single, continuous time above about 17 ng/ml from about 11to about 15 hours.
 15. The pharmaceutical dosage form of claim 11,wherein the subject has a single, continuous time below about 17 ng/mlfrom about 9 to about 13 hours.
 16. The pharmaceutical dosage form ofclaim 8, wherein the subject has a mean maximum plasma concentration(Cmax) from about 3 ng/mL per mg to about 6 ng/mL per mg of tofacitinibdosed.
 17. The pharmaceutical dosage form of claim 8, wherein saiddosage form delivers the tofacitinib, or pharmaceutically acceptablesalt thereof, by a system selected from the group consisting of anextrudable core system, a swellable core system, and an asymmetricmembrane technology.
 18. The pharmaceutical dosage form of claim 8wherein said cellulose derivative is cellulose acetate.
 19. Thepharmaceutical dosage form of claim 8, wherein said coating furthercomprising a water soluble polymer having an average molecular weightbetween 2000 and 100,000 daltons.
 20. The pharmaceutical dosage form ofclaim 19, wherein said water soluble polymer is selected from the groupconsisting of water soluble cellulose derivatives, acacia, dextrin, guargum, maltodextrin, sodium alginate, starch, polyacrylates, and polyvinylalcohols.
 21. The pharmaceutical dosage form of claim 20, wherein saidwater soluble cellulose derivatives comprises hydroxypropylcellulose,hydroxypropylmethylcellulose or hydroxyethylcellulose.
 22. Thepharmaceutical dosage forms of claim 8, wherein the osmagen is a sugar.23. The pharmaceutical dosage form of claim 22, wherein the sugar issorbitol.
 24. The once daily pharmaceutical dosage form of claim 8wherein the subject has a mean steady-state minimum plasma concentration(Cmin) less than about 0.3 ng/mL per mg of tofacitinib dosed.
 25. Theonce daily pharmaceutical dosage form of claim 8, wherein whenadministered orally to the subject has a mean fed/fasted ratio of thearea under the plasma concentration versus time curve from about 0.7 toabout 1.4 and a mean fed/fasted ratio of the maximum plasmaconcentration (Cmax) from about 0.7 to about 1.4.